Review
Forceful patterning: theoretical principles of
mechanochemical pattern formation
Jan Rombouts1,2,*,† , Jenna Elliott1,3,† & Anna Erzberger1,3,**
Abstract
Biological pattern formation is essential for generating and main-
taining spatial structures from the scale of a single cell to tissues
and even collections of organisms. Besides biochemical interac-
tions, there is an important role for mechanical and geometrical
features in the generation of patterns. We review the theoretical
principles underlying different types of mechanochemical pattern
formation across spatial scales and levels of biological organization.
Keywords geometry; mechanics; morphogenesis; pattern formation; theory
Subject Categories Cell Adhesion; Polarity & Cytoskeleton; Computational
Biology; Signal Transduction
DOI 10.15252/embr.202357739 | Received 30 June 2023 | Revised 21 September
2023 | Accepted 27 September 2023 | Published online 2 November 2023
EMBO Reports (2023) 24: e57739
Introduction
The spontaneous generation of spatial structures is a hallmark of
living matter that enables biological function from the molecular to
the organismal scale. Indeed, patterns are some of the most conspic-
uous and beautiful features of the biological world. Markings on
animal skins are a famous example, but there is a wide variety of
systems that exhibit pattern formation. Fig 1A shows some exam-
ples in which pattern formation relies on mechanical processes. On
the micrometer scale, patterns in the cytoskeleton at the surface of
the cell emerge from active contractile stresses generated by molecu-
lar motors (Salbreux et al, 2012; Reymann et al, 2016). Tissue-scale
patterns arise from the interplay between cell signaling and mechan-
ical cell–cell interactions (Hino et al, 2020; Boocock et al, 2021).
Mechanical interactions can drive morphogenesis as exemplified by
the hexagonal patterns on the skin of avian embryos that instruct
feather placement (Shyer et al, 2017; Curantz et al, 2022; Palmquist
et al, 2022). Multiple organisms form patterns on scales of millime-
ters to centimeters, for example, through constrained growth in bac-
terial biofilms (Gordon et al, 2017; Yan et al, 2019) or
1 Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
2 Developmental Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
3 Department of Physics and Astronomy, Heidelberg University, Heidelberg, Germany
*Corresponding author. Tel: +49 6221 387 8367; E-mail: jan.rombouts@embl.de
**Corresponding author. Tel: +49 6221 387 8522; E-mail: erzberge@embl.de
†
These authors contributed equally to this work
ª 2023 The Authors. Published under the terms of the CC BY 4.0 license.
hydrodynamic and contact-based interactions in collections of nem-
atodes (Peshkov et al, 2022). These patterns have different functions
in cellular contexts, the development and maintenance of an organ-
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
ism, or in the collective organization of multiple organisms. To
obtain more insight into these functions, an understanding of the
biochemical and mechanical aspects that control pattern formation
is essential.
In the following, we introduce some of the theoretical concepts
used to study pattern formation. We consider patterns as regular
spatial features that consist of many units (e.g., cells or molecules),
where the characteristic length scale of the pattern is much larger
than the size of a single unit. A pattern can be structural, character-
ized by a regular shape, or it can manifest as regular variations in
concentration or density. Typically, a pattern consists of repeated
features. In that case, we identify a pattern’s length scale with its
wavelength, that is, the distance between repeated features. We
refer to the length scale of individual units ‘ as microscopic and the
pattern length scale λ as mesoscopic, relative to the macroscopic
size L of the whole system (Fig 1B).
Not all details of a system’s individual microscopic units are rele-
vant for determining its mesoscopic features. When the spatial
scales are well separated (i.e., when λ≫‘), the large number of
microscopic units that make up a wavelength of the pattern permits
a statistical description. An example of such a description is a con-
centration field that keeps track only of the average number of units
per length, area, or volume at each point in space and time. A sepa-
ration of spatial scales, in many cases, also implies a separation of
temporal scales. Indeed, the mean collision time of water molecules
within a typical ocean wave with a period of 10 s is below 10
10 s.
Within the actin cortex at the cell surface, typical timescales of mac-
romolecular interactions are on the order of milliseconds, whereas
they lead to cell-level shape dynamics and flows on the minute-to-
hour scale (Salbreux et al, 2012; Bergert et al, 2015; Reymann
et al, 2016). Under such circumstances, a system can be described
in the continuum limit in terms of field variables that evolve in time.
The mesoscopic parameters that characterize the continuum level
can be estimated from the microscopic dynamics. For example, the
coarse-grained viscoelastic properties of multicellular aggregates can
EMBO reports 24: e57739 | 2023 1 of 24
EMBO reports
List of symbols
In the text, bold symbols indicate vector or tensor quantities. A subscript 0 indicates a steady-state quantity. A tilde indicates a small perturbation from
steady state.
x, y, z space coordinates
t time coordinate
L domain length
R radius
Γ two-dimensional surface
A surface area
H mean curvature
λ pattern wavelength
q wavenumber
ω growth rate
‘ microscopic length
c concentration
j flux
v velocity
be related to the microscopic parameters of cellular interactions
(Oriola et al, 2022).
If a system is made up of a small number of constituents, or if the
focus is on individual interactions, a discrete framework might be a
more appropriate description. Discrete modeling frameworks can be
used to study, for example, the dynamics of individual cytoskeletal
filaments and associated proteins (Nedelec & Foethke, 2007) or inter-
actions between cells (Graner & Glazier, 1992; Alt et al, 2017; pre-
print: Belousov et al, 2023). Additionally, discrete models are also
essential to describe systems where the length scale of the pattern is
similar to the length scale of the individual units (e.g., Collier
et al, 1996; Manukyan et al, 2017; Fofonjka & Milinkovitch, 2021). In
this paper, however, we focus on continuum approaches to pattern
formation. Continuum theories have successfully predicted large-
scale flows, deformations, and patterns in many cellular and multi-
cellular systems (Bergert et al, 2015; Streichan et al, 2018; Erzberger
et al, 2020; Saadaoui et al, 2020; Palmquist et al, 2022).
The dynamics in space and time of mesoscale fields, such as con-
centrations, follow partial differential equations that are called conti-
nuity equations. When the fields correspond to densities of
conserved quantities such as mass or momentum, the governing
partial differential equations express conservation laws. For exam-
ple, the concentration c of a conserved number of molecules at posi-
tion x and time t evolves according to the spatial derivatives of the
flux density j at that point:
∂t cðx; tÞ ¼
r  j:
This equation states that the change in c depends on how many
molecules enter and exit at a certain location. The r operator
can be expressed in terms of spatial derivatives, and in one dimen-
sion is equal to ∂x . The flux density j can arise, for example,
from diffusion, which for molecules usually obeys Fick’s law:
jdiffusive ¼
Drc (Fick, 1855). Plugging the diffusive flux into equa-
tion (1) leads to the familiar diffusion equation ∂t c ¼ Dr2 c. The
same equation can be used for collections of cells, rather than mol-
ecules, that are moving about randomly (Berg, 1993).
In many biological contexts, the total number of units is not con-
served. For example, cells and organisms reproduce and die, and
2 of 24 EMBO reports 24: e57739 | 2023
Jan Rombouts et al
σ stress
f external force
h height function
r displacement
φ oscillator phase
R reaction term
F free energy
D diffusion coefficient
η viscosity
γ surface tension
τ timescale
α friction coefficient
κ bending rigidity
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
Cp spontaneous curvature
molecules are subject to chemical reactions. Such processes lead to
reaction terms RðcÞ in the equation for the corresponding density or
concentration that describes how c changes locally. Such reaction–
diffusion equations
∂t c ¼ Dr2 c þ RðcÞ (2)
are classical pattern-forming systems. The seminal work of
Turing (1952) showed how biochemical feedback mechanisms com-
bined with diffusion can lead to the emergence of regular patterns.
Turing’s work was conceptually extended and described in the con-
text of activator–inhibitor systems (Gierer & Meinhardt, 1972; Mein-
hardt, 2012). Such systems need at least two chemical species to
form patterns (see Box 1 for an example). Turing’s original two-
species example is mathematically simple but has often been consid-
ered biologically unrealistic due to, for example, its sensitivity to
parameter values (Green & Sharpe, 2015). Recent theoretical and
computational work has shown, however, that a Turing mechanism
can robustly produce patterns in more complex reaction–diffusion
systems (Marcon et al, 2016; Haas & Goldstein, 2021).
In most biological systems, patterns are not due to biochemical
or genetic interactions alone. Mechanical forces play an important
role. The propagation of mechanical stresses occurs on different
temporal and spatial scales than molecular diffusion. For example,
a small molecule requires seconds to diffuse over a 10-100 µm dis-
tance, whereas mechanical stress propagates over a similar dis-
tance within microseconds in the cytoskeleton (Wang et al, 2009).
(1) Mechanical or mechanochemical pattern formation thus broadens
the range of scales on which patterns can be formed (Howard
et al, 2011; Collinet & Lecuit, 2021). In fact, since all organisms
and cells are subject to physical laws, the effects of these laws are
likely exploited for the generation of patterns with biological
functions.
An aspect that is inherently linked to mechanics is the size and
geometry of the domain on which these patterns form, such as the
shape of cell membranes or tissue layers. Spatial derivative opera-
tors, such as r, take different forms depending on the dimension of
the system, its geometric properties, and the chosen coordinate sys-
tem. This, in turn, influences the types of spatial modes that are
used in a linear stability analysis (see Box 1) and the patterns that
 2023 The Authors
Jan Rombouts et al EMBO reports

10 μm 100 μm 1 mm 10 mm
B D O = 2π/qmax
System size L

exp(Zt) sin(qmaxx)

Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.

Pattern wavelength O Particle size t

C q = π/L q =1.3π/L
x
L E

q = 2π/L exp(Zt) Z

q =3π/L F
Zmax
Re(Z)

q
qmax

Figure 1. Mechanochemical pattern formation across scales.

(A) From left to right: Myosin patterns at the surface of C. elegans embryos (Reymann et al, 2016), ERK waves in MDCK monolayers (Lin et al, 2022), cell density patterns
in penguin skin (Curantz et al, 2022), buckled biofilm (Yan et al, 2019), and collective configuration of nematodes (preprint: Quillen et al, 2021a). (B) Within a system of
size L, the wavelength of a pattern λ is larger than the size of individual units ‘. (C) A pattern in a system with size L and fixed values at the boundaries can only
contain modes with wavenumbers that are integer multiples of π=L; other modes do not fulfill the boundary conditions (red dotted line). The dimension and shape of
the domain matter for the spatial modes: a pattern can be expanded into a linear combination of sinusoidal modes on a one-dimensional domain (left) and into a com-
bination of spherical harmonic modes on a spherical domain (right). (D, E) When a field develops an instability from a uniform steady state, linear stability analysis
reveals the dominant length scale λ ¼ 2π=qmax that appears first. This mode qmax has the fastest growth rate ReðωÞ, that is, it is at the maximum of the dispersion rela-
tion. (F) The dispersion relation for equation (20) reveals the temporal dynamics of different modes: regions where ωðqÞ is positive or negative correspond to growing or
decaying modes, respectively. If there are unstable modes, that is, ReðωÞ > 0 for some q, there is an instability that can lead to patterns.

can appear. Moreover, the shape of the domain can influence the
dynamics of the pattern: Nishide & Ishihara (2022) recently showed
that Turing-type patterns that are static on a flat domain can propa-
gate on curved shapes.
Furthermore, mechanical forces affect the flux term in equa-
tion (1). For example, if there are fluid flows in the system that
carry along molecules or cells, there is a contribution of an advec-
tive flux jadvective ¼ cv, where v is the velocity field. The evolution of
v is governed by a second equation that states the conservation of
momentum. This equation can be derived in the same way as equa-
tion (1), but luckily, it can be simplified for many biological
contexts by neglecting the time-derivative term on the left-hand side
because, on the scale of cells and small organisms, forces due to
friction, or viscosity, dominate over inertial forces. Such over-
damped motion appears very different from our everyday experi-
ences (Purcell, 1977; Lauga & Powers, 2009). In this limit, the
conservation law for momentum can be written as
0 ¼ r  σ tot þ f; (3)
in which f denotes any external forces, such as those arising from
friction with the environment. Equation (3) is a continuity

 2023 The Authors EMBO reports 24: e57739 | 2023 3 of 24

EMBO reports Jan Rombouts et al

Box 1. Linear stability analysis of partial differential equations.

Linear stability analysis (LSA) provides insights into the behavior of a system from its steady states and their stability. A system is in a steady state if
it is not changing over time. If this state is stable, the system will return to it after being perturbed. If there exists at least one perturbation to
the steady state which grows in time, leading the system away from it, the steady state is called unstable. As an example, we consider a reaction–dif-
fusion system (see equation 2) in one dimension, the Schnakenberg system (Schnakenberg, 1979; Murray, 1982). This is a pattern-forming system of
purely chemical origin. Two chemicals A and B react and diffuse, and the evolution of their concentrations is given by

∂t A ¼ DA ∂xx A þ k1 A2 B þ k2
k3 A;
( 18)
∂t B ¼ DB ∂xx B
k1 A2 B þ k4 :

The terms with the spatial derivatives describe diffusion with diffusion constants DA and DB and the remaining terms describe the chemical reactions.
The chemical species A and B are produced at constant rates k2 and k4 , respectively. There is a conversion reaction with rate constant k1 , and A is
degraded with rate constant k3 . Appropriate scaling of the variables, space, and time yields equations in terms of the dimensionless variables u and v

∂t u ¼ ∂xx u þ Ru ðu; vÞ ¼ ∂xx u þ α
u þ u2 v;

( 19)
∂t v ¼ d∂xx v þ Rv ðu; vÞ ¼ d∂xx v þ β
u2 v;

Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.



with only three dimensionless parameters: α ¼ k1=2 3=2 1=2 3=2
1 k2 =k3 , β ¼ k1 k4 =k3 , and the ratio of diffusion coefficients d ¼ DB =DA .
To analyze the system, we first identify the spatially uniform steady states—for which Ru ðu; vÞ ¼ 0 and Rv ðu; vÞ ¼ 0—and then determine their sta-
bility to spatial perturbations. In real systems, such perturbations are typically due to noise. For the Schnakenberg equations (19), there is a single
steady state given by u0 ¼ α þ β and v0 ¼ β=ðα þ βÞ2 . To analyze its stability, we derive how small perturbations from this steady state, u ~ and ~v,
evolve over time. Substituting u ¼ u0 þ u ~ and v ¼ v0 þ ~v, we obtain

∂t u~ ≈ ∂xx u
~ þ ∂u Ru ðu0 ; v0 Þ~
u þ ∂v Ru ðu0 ; v0 Þ~ v
( 20)
∂t ~v ≈ d∂xx ~ ~ þ ∂ v R v ð u 0 ; v0 Þ ~
v þ ∂u Rv ðu0 ; v0 Þu v;

in which we have kept terms in linear order in the small perturbations. In this linearized version, one can already see the feedback loops that are act-
ing in the system. For example, ∂v Ru ðu0 ; v0 Þ ¼ ðα þ βÞ2 is positive, indicating that there is positive feedback from B to A.
This linear system can be solved for any initial condition by decomposing the initial spatial profile into a sum of spatial modes and studying the
temporal evolution of these modes. The spatial modes that are appropriate depend on the geometry of the system. In this one-dimensional example,
suitable spatial modes are the functions cosðqxÞ and sinðqxÞ for different wavenumbers q. As known from Fourier analysis, a profile can be decom-
posed into combinations of these functions. These spatial modes are appropriate because their shape (but not their amplitude) is unchanged when
applying the diffusion operator ∂xx . This, together with the linearity of the equation, allows to study the evolution of equations (20) by solely consider-
ing what happens to the spatial modes. The temporal evolution of an initially sinusoidal profile is given by eωt sinðqxÞ and eωt cosðqxÞ. Each of the
modes’ amplitude thus evolves as eωt (Fig 1D and E). The value of ω depends on the wavenumber q. The relation ωðqÞ is called the dispersion relation
and can be computed from equations (20). This relation describes the growth rates of the different spatial modes (Fig 1F). Generally, ωðqÞ is a complex
number. Its real part describes the growth of the mode: perturbations with ReðωÞ < 0 decay in time, leaving the uniform solution intact. However, if
for a given q, one of the growth rates has a positive real part; the amplitude of the perturbation eωt grows in time. This implies that the uniform
steady state is unstable to perturbations with wavenumber q. The formation of patterns is associated with the existence of non-zero wavenumbers
that have ReðωÞ > 0. The fastest-growing mode—at the maximum of the dispersion relation—dominates, and thus sets the initial spatial wavelength
of the pattern. If ωðqÞ has an imaginary part, the solution is oscillatory over time. A mode that is growing in amplitude and is oscillatory leads to spa-
tiotemporal patterns such as waves, whereas a purely real ω is associated with stationary patterns. The dispersion relation of the Schnakenberg sys-
tem reveals the conditions on α; β, and d that lead to pattern formation, that is, for which values of these parameters unstable modes with q > 0
exist.
The geometry and size of the system impose further conditions on the solutions, mainly by constraining the form of the spatial modes and avail-
able wavenumbers. The sinusoidal form of the spatial modes is imposed by the fact that we study a one-dimensional system. The particular wave-
numbers that are possible are dictated by the domain size and boundaries: if the chemical reactions of the Schnakenberg system happen on a closed
interval ½0; L with either fixed concentrations or no-flux conditions at the boundaries, the only possible wavenumbers are of the form q ¼ nπ=L, with
an integer n. Patterns appear only when one of the permitted non-zero modes has a positive growth rate. The size of the domain thus restricts which
wavenumbers are possible. Analogously, other domain shapes and sizes dictate the spatial modes that can become unstable. This is illustrated in
Fig 1C.
Since we assumed small perturbations to the steady state in going from equations (19) to (20), the linear stability analysis only reveals the dynam-
ics of systems that are close to a steady state. Once the perturbation becomes too large, non-linear effects come into play and analytical results are
hard to obtain. Moreover, non-linear terms in the equations dictate at which amplitude the growing perturbations saturate, and also determine which
types of patterns appear; for example, whether spots or stripes appear in two-dimensional systems. Finally, we note that not all patterns exist close to
a homogeneous steady state—patterns may also exist “far from threshold” and depend crucially on the non-linearities in the system. We refer to the
book by Cross & Greenside (2009) for more details about these aspects. Even with these caveats, in many cases, the linear stability analysis already
provides good insight into the system’s pattern-forming properties and leads to an understanding of which biological parameters determine the exis-
tence and characteristic scale of patterns, as we illustrate throughout this review.

equation like equation (1), where the time derivative of the veloc- term. The counterpart of j in equation (1) is written as the negative
ity on the left-hand side is zero. In the same way in which we keep momentum flux density by convention and is called the total stress
track of how particles enter and leave a location in equation (1), tensor σ tot . It describes all forces per area that act on a small piece
we must account for the transport of momentum through a flux of the material for each of the possible force directions. Same as

4 of 24 EMBO reports 24: e57739 | 2023  2023 The Authors

Jan Rombouts et al
for the molecular flux density, the components of the stress tensor
depend on the properties of the system. In an incompressible New-
tonian fluid, for example, a viscous stress arises between adjacent
fluid layers that is proportional to the velocity difference between
the layers. Additionally, in most biological systems, there are
active contributions to the stress, σ active (Kruse et al, 2005; Jülicher
et al, 2018), generated by processes such as the ATP-fuelled
motion of molecular motors within the cytoskeleton (Bois et al,
2011; Dasanayake et al, 2011; Peleg et al, 2011), or the
self-propelled movement of migrating cells or swimming
microorganisms (Yeomans, 2017; Alert & Trepat, 2020). Such
active processes are characteristic of biological systems and can
give rise to behavior not seen in passive materials. This aspect of
living systems motivated many successful developments within the
research field of active matter physics, with relevance beyond biol-
ogy (Ramaswamy, 2010; Marchetti et al, 2013; Needleman &
Dogic, 2017; Bowick et al, 2022).
An equation for force balance can also be derived starting from
energy-minimization considerations, where a force is induced by a
system moving toward configurations of lower energy (see, e.g.,
section “Pattern formation by membrane curvature”).
Once the governing equations of a system have been determined,
we can analyze whether they admit pattern formation. One way of
doing this is to simulate the time evolution of the equation on a
computer and see whether patterns appear over time. Additionally,
an analytical method called linear stability analysis is useful to
obtain conditions on pattern formation and estimates of typical pat-
tern length scales (see Box 1, or the book by Murray (2003) for a
more detailed explanation).
Pattern formation typically arises due to different kinds of feed-
back mechanisms between the variables of the system. Positive
feedback implies a self-reinforcing coupling between chemical or
mechanical variables which leads to the amplification of small per-
turbations over time, whereas negative feedback inhibits the growth
of perturbations. Typically, both positive and negative feedbacks are
present in pattern-forming systems: positive feedback amplifies per-
turbations that lead to patterns, but negative feedback prevents
these from increasing unboundedly. Additionally, negative feed-
backs are often associated with oscillatory dynamics, which in spa-
tially extended systems can lead to waves (see Beta & Kruse (2017)
and section “Waves through mechanosensing”).
In the following, we review some of the main patterning phe-
nomena involving mechanics and shape, and focus on the underly-
ing theoretical principles. We selected examples in which the
outlined continuum framework and linear stability analysis can be
applied, and mainly consider patterns that arise from the instability
of a uniform steady state. We begin by discussing the role of geome-
try in the development of protein patterns at the surface of cells,
covering aspects such as bulk-surface coupling and membrane–
curvature interactions. We then discuss patterns generated by
contractile instabilities, where active contractile elements produce
self-convecting flows. The universal nature of this pattern-forming
mechanism is highlighted by its relevance both at the subcellular
and at the multicellular level. Next, we briefly discuss purely
mechanical interactions such as buckling, and how these can lead to
periodic patterning. Finally, we discuss waves, which are examples
of patterns that show both temporal and spatial variation. We
describe two different types of waves: one mechano-chemical and
 2023 The Authors
EMBO reports
one based on the synchronization of oscillators due to hydrody-
namic effects. The selected examples are ordered roughly along
increasing spatial scales and levels of biological organization from
subcellular to organismal.
Geometry-dependent reaction–diffusion patterns
Pattern formation at the cell surface is coupled to shape and curva-
ture and is influenced by the biophysical properties of the cell mem-
brane and the cytoskeleton. In particular, reaction–diffusion
dynamics in cells often involve an exchange of components between
structures at the cell surface, that is, the plasma membrane or the
actomyosin cortex, and the cytosol. These fluxes give rise to bio-
chemical couplings between nearly two-dimensional structures that
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
can be approximated as surfaces and a three-dimensional bulk.
Generally, the three-dimensional geometry of a cell has an impor-
tant influence on biochemical reactions, both in the cytoplasm and
on cell membranes. The dependence of biochemical patterns on cel-
lular geometry enables shape sensing: the process by which shape
information is incorporated into, and used to instruct, cellular
processes.
Such a shape-sensing mechanism has been proposed as the func-
tion of certain protein patterns at the cell surface. For example, Min
proteins undergo patterning at the surface of E. coli bacteria (de
Boer et al, 1989; Wettmann & Kruse, 2018; Fig 2A). Here, a standing
wave oscillation in the concentrations of Min proteins provides a
means of localizing the center of the cell (de Boer et al, 1989;
Lutkenhaus, 2007). This standing wave templates the formation of a
contractile protein ring to ensure symmetric cell division.
The spatial distribution of Min proteins evolves according to
coupled reaction–diffusion equations that consist of both cytosolic
and membrane-bound components. Early observations of this sys-
tem in division-inhibited bacteria showed that the concentration of
a membrane-bound Min protein formed standing waves in elon-
gated cells (Hu & Lutkenhaus, 1999; Raskin & de Boer, 1999), and
such waves were later also observed in vitro in closed geometries
(Zieske & Schwille, 2013). In comparison, on flat membranes, the
Min system produces traveling and spiral waves and many other
pattern structures (Loose et al, 2008; Ivanov & Mizuuchi, 2010;
Denk et al, 2018).
A brief form of the reaction–diffusion system can be written in
terms of a vector of cytosolic components c and a vector of
membrane-bound components m (Huang et al, 2003; Halatek &
Frey, 2012). The cytosolic molecules diffuse in the three-
dimensional bulk with coefficient Dc , and the membrane-bound
molecules diffuse on the two-dimensional boundary surface Γ with
coefficient Dm . The equations read
∂t c ¼ Dc r23D c þ Rc ðcÞ; (4)
 
∂t m ¼ Dm r22D m þ Rm cjΓ ; m : (5)
The reaction terms Rc and Rm describe the chemical reactions in
the cytosol and between bulk and surface components, where cjΓ
indicates the cytosolic concentrations at the membrane–cytosol
boundary. A minimal reaction schematic for these reactions is
depicted in Fig 2B.
EMBO reports 24: e57739 | 2023 5 of 24
EMBO reports Jan Rombouts et al

A B

Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.

C D
μ μ μ

Figure 2. Min patterns can sense cell shape.

(A) Sketch of MinD oscillation (top) and images of MinD in E. coli, showing oscillations in a live cell (bottom), adapted from Bonny et al (2013). Scale bar: 3μm. (B)
Schematic representations show the compartment geometry (left) with components of the Min reaction–diffusion system in the cytosol (blue) and bound to the surface
Γ (green), and a diagram of a minimal Min reaction model (right), adapted from Meindlhumer et al (2023). (C) Setup of the double-membrane configuration (left). A top
membrane (orange) is separated by a cytosolic volume with height h from a lower membrane (blue). The observed patterns change as h is varied. Kymographs from sim-
ulations show a decrease in the coupling between patterns at the two surfaces for increasing separation heights (right), where h ¼ 5μm is the critical height above
which non-standing wave patterns emerge. Adapted from Brauns et al (2021). (D) Sketches visualizing the unstable (blue) and stable (gray) perturbation modes of a sin-
gle wavenumber q at large and small membrane separations. For small separations, the antisymmetric mode is stable and therefore does not contribute to pattern
emergence. (E) Simulation results showing Min oscillations along symmetry axes of confining shapes (from Wettmann et al, 2018).

The dynamics in the bulk are coupled to those on the surface
through a boundary condition accounting for particle conservation:
the flux of particles leaving and entering the cytosol is balanced by
the rates of membrane binding and unbinding. Modeling details,
including cooperative binding (Loose et al, 2008), further biochemi-
cal reactions (Meinhardt & Boer, 2001; Loose et al, 2011; Park
et al, 2011; Ayed et al, 2017; preprint: Carlquist & Cytrynbaum,
2021), protein polymerization (Drew et al, 2005; Cytrynbaum &
Marshall, 2007), interactions with particular lipids localized at the
cell poles (Renner & Weibel, 2012), and advective cytoplasmic flows
(Vecchiarelli et al, 2014; Meindlhumer et al, 2023), have been exten-
sively studied and are proposed to play important roles in regulating
Min patterns (Vecchiarelli et al, 2016; Wettmann & Kruse, 2018;
Ramm et al, 2019; Takada et al, 2022).

6 of 24 EMBO reports 24: e57739 | 2023  2023 The Authors

Jan Rombouts et al
The Min reaction system includes an ATPase, MinD, that enhances
the recruitment of itself to the membrane and a second protein, MinE,
which drives MinD off the membrane again (Wettmann & Kruse, 2018;
Ramm et al, 2019). Under specific in vitro conditions, such systems
have been shown to exhibit stationary patterns (Glock et al, 2019), but
most research focuses on their emergent oscillatory dynamics. These
have been proposed to arise from a difference in the time MinD and
MinE spend in the cytosol before re-binding to the membrane, intro-
duced by the time needed for nucleotide replenishment of the ATPase
MinD (Huang et al, 2003; Glock et al, 2019). Whereas in vitro, this sys-
tem admits different types of oscillating patterns, including both travel-
ing waves and standing waves, in vivo cells robustly produce standing
waves (Fig 2A; Hu & Lutkenhaus, 1999; Raskin & de Boer, 1999; Bonny
et al, 2013). Different groups have shown that the geometry of the cell
may play a crucial role in the robust selection of standing wave patterns
(Schweizer et al, 2012; Zieske & Schwille, 2013, 2014; Wu et al, 2015).
Although the exact mechanism behind the emergence of patterns in dif-
ferent geometries is still under debate (Park et al, 2011; Halatek &
Frey, 2012; Halatek et al, 2018; Wettmann & Kruse, 2018; Ramm
et al, 2019; preprint: Carlquist & Cytrynbaum, 2021; Takada et al,
2022), protein depletion has been suggested to play an important role
in the formation of standing waves (Vecchiarelli et al, 2016), and
Brauns et al (2021) propose that this arises due to the narrow geometry
of the cells. The boundary condition for the cytosolic concentrations
enforces protein conservation. In a small cytosolic volume, such as in
the narrow in vivo geometry, the flux of particles from the cytosol onto
the membrane leads to cytosolic protein depletion.
To understand how changes in system geometry can lead to tran-
sitions between patterning regimes, Brauns et al (2021) considered a
particular configuration in which two flat, extended membranes are
separated by a variable volume of cytosol (Fig 2C). As discussed in
Box 1, the size and shape of the patterning domain determines which
perturbation modes are available to a system. Here, the geometric
configuration restricts the perturbations to be periodic parallel to the
membrane, and either symmetric or asymmetric in the perpendicular
direction (Fig 2D). Crucially, linear stability analysis shows that it is
the separation distance between the two membranes that determines
which of these perpendicular modes grow over time, and what type
of patterns the system supports. This introduces a dependence on
geometry to the patterning process. Below a critical value of mem-
brane separation, only the symmetric mode perturbations undergo
growth. This results in the same cytosolic concentration dynamics at
the two membranes and leads to standing wave patterns.
Above the membrane separation threshold, the antisymmetric
modes also grow in time and therefore the protein concentrations at
the two membranes are no longer constrained to be equal. In this
regime, many more perturbation modes exhibit growth and the
interactions with a bulk supply of proteins in the cytosol can lead to
the emergence of many different types of patterns.
The geometry of the boundaries thus controls the type of patterns
that appear in the Min system. Brauns et al (2021) confirmed these
predictions qualitatively through simulations (Fig 2C) and in experi-
ments, using a microfluidic system with variable chamber height.
These results suggest that in vivo, the narrow radius of the cylindri-
cal bacteria provides the geometrical constraint on Min patterns that
allows the formation of standing waves.
The Min system is a classic and accessible pattern-forming sys-
tem. This is one of the reasons it is often used as a testing ground
 2023 The Authors
EMBO reports
for theories on (biological) pattern formation, also beyond linear
stability theory (Halatek & Frey, 2018; Brauns et al, 2020; Würthner
et al, 2022). This system is also an example of a “mass-conserving
reaction diffusion system,” where spatial redistribution, such as pro-
tein depletion, drives the emergence of protein patterns. For a more
detailed discussion of these systems, and their comparisons with
non-mass conserving systems, see Halatek et al (2018).
In elongated, rod-like cells such as E. coli, the standing waves
produced by the Min system provide a mechanism to read out the
mid-line and determine the cell division plane. A natural question is
then which Min patterns form in non-rod-like cells. Wu et al (2015)
put E. coli cells in microchambers with different shapes, and
observed that Min patterns oscillated along one of the symmetry
axes. Subsequent simulations by Wettmann et al (2018) have also
matched these results (Fig 2E). Walsh et al (2019) studied archaeal
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
cells, where the division plane is also determined by a Min system.
They focused on nearly triangular cells in particular and observed
that the division plane corresponds to what is predicted by an analy-
sis of the spatial modes determined by the cell shape. These exam-
ples also show how shape is a fundamental property that can guide
the biochemical machinery of the cell.
Min patterns thus respond to global properties of cell shape. By
contrast, patterns at the surface of starfish oocytes have been pro-
posed to act as “local” shape sensors (Wigbers et al, 2021). In these
cells, the angle of the membrane relative to the direction to the
nucleus, and its distance from the nucleus, are sensed through a pro-
tein concentration gradient. Similarly to the embryos of several other
species (Sawai, 1982; Yoneda et al, 1982; Quaas & Wylie, 2002), star-
fish oocytes feature a contraction wave along their membrane before
cell division, which starts at the vegetal pole (far from the nucleus)
and travels to the animal pole (close to the nucleus; Hamaguchi &
Hiramoto, 1978; Klughammer et al, 2018). This traveling wave ends
at the animal pole regardless of the oocyte shape, implying a modula-
tion of the wave speed according to local cell shape (Bischof
et al, 2017). Wigbers et al (2021) proposed a speed modulation mech-
anism for this traveling wave in the form of a temporally decaying
protein concentration profile in the cytosol. The concentration has a
maximum at the nucleus and decreases linearly with distance away
from it. If the nucleus is not perfectly centered in the cell, the protein
concentration will be different at different points on the cell surface.
This links the cell’s biochemistry to its geometry. The protein concen-
tration’s temporal decay at the membrane then guides the progression
of the contractile wave and forces the wave speed to adapt to local
membrane geometry. Together with the fact that the cell is closed, this
ensures that the wave always ends at the animal pole. This system
thus provides a means of local shape sensing.
Min patterns and surface contraction waves in oocytes both
show how biochemical reactions may couple to cell geometry
through interactions between the three-dimensional cytosol and the
two-dimensional membrane. Overall, these examples demonstrate
how biochemical reaction–diffusion systems are influenced in
important ways by the geometric features of the cell.
Pattern formation by membrane curvature
In the previous section, we discussed how the patterning dynamics
of biochemical reaction–diffusion systems are modulated by the
EMBO reports 24: e57739 | 2023 7 of 24
EMBO reports
geometry of the system. Many cellular patterning processes, how-
ever, rely on two-way interactions between the biochemical reac-
tions and the biophysical properties of the structures they take place
on (Schamberger et al, 2023). In this section, we discuss how mem-
brane biophysics “by itself” can drive protein patterning. In particu-
lar, the localization of proteins to and/or transport of proteins on
the plasma membrane can depend on the curvature of the mem-
brane (Heinrich et al, 2010; Sorre et al, 2012; Kwiecinski et al,
2017). Additionally, membrane–protein interactions modulate the
local biophysical properties of the membrane, giving rise to feed-
back effects that can drive pattern formation (Cooke & Deserno,
2006; Reynwar et al, 2007; Yue et al, 2010; Ramakrishnan
et al, 2014; Sodt & Pastor, 2014; Hossein & Deserno, 2020). For
example, curvature-mediated pattern formation plays a role in the
formation of cellular protrusions, such as those involved in cell
migration or myelination-like coiling. There, proteins such as
curved BAR proteins couple to membrane shape and interact with
the actin cytoskeleton, producing dynamic patterns and protrusions
on the cell surface (Simunovic et al, 2015; Carman & Domin-
guez, 2018; Gov, 2018; Wu et al, 2018; Begemann et al, 2019; Sadhu
et al, 2021, 2023; Ravid et al, 2023).
On length scales much larger than its thickness, a membrane can
be approximated as a two-dimensional sheet with a resistance to
bending (Ramakrishnan et al, 2014; Deserno, 2015). This resistance
is a mesoscopic biophysical consequence of the microscopic phos-
pholipid structure of the layer (Bloom et al, 1991; Alberts
et al, 2002): bending the membrane causes the lipid heads on one
side of the bilayer to be pushed together, and to be pulled apart on
the other, which results in an energetic cost for high curvatures
(Würger, 2000; Kurtisovski et al, 2007).
The curvature of a two-dimensional sheet at a given point can be
described completely by its two principal radii of curvature, R1 and
R2 , which in turn define the mean curvature, H (Fig 3B). The mem-
brane bending energy written to quadratic order in the curvature is
called the Helfrich Hamiltonian (Canham, 1970; Helfrich, 1973;
Deserno et al, 2014; Tu & Ou-Yang, 2014; Guckenberger & Gekle,
2017; Alimohamadi & Rangamani, 2018). For membranes with no
holes and negligible edge effects, it takes the form
Z
1  2
F Bending ¼ dA κ 2H
C p ; (6)
2 however, the local change of curvature imposed by the proteins can
which integrates the squared deviations of the mean membrane
curvature H (Fig 3B) from a preferred value C p over the membrane
area A. The bending rigidity κ characterizes the resistance of the
membrane to bending (Dimova, 2014; Doktorova et al, 2017;
Doskocz et al, 2018), and is related to the membrane persistence
length (De Gennes & Taupin, 1982; Peliti & Leibler, 1985; Gutjahr
et al, 2006). Here, for simplicity, we consider a system where sur-
face tension and other energetic contributions have been neglected
(see Agudo-Canalejo & Golestanian, 2017; Tozzi et al, 2019, for
examples where further energetic contributions have been considered).
The energetically most favorable membrane shape minimizes an
energy functional F such as equation (6). For shapes described by a
height function hðx; y; tÞ (Fig 3A), this equilibrium shape is the solu-
tion to the equation 0 ¼ δF=δh, and it would be observed in a sys-
tem at rest. The variational derivative δF=δh describes how a
functional such as the bending energy changes for different shape
8 of 24 EMBO reports 24: e57739 | 2023
Jan Rombouts et al
functions h. Membrane shape dynamics arise when the system does
not reside in this preferred configuration. Then, a restoring force
that is proportional to δF=δh close to equilibrium drives the mem-
brane toward the preferred configuration. This term may compete
with other forces acting on the membrane. With the inclusion of
frictional forces, a force balance equation (equation 3) governing
the membrane shape dynamics can be written as
δF
α∂t h ¼
: (7)
δh
Here, the left-hand side describes the frictional force on the membrane
due to movement, with friction coefficient α, and the right-hand side
corresponds to the forces arising from the free energy gradient. We
continue to consider a simple theory for demonstration purposes,
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
where we have neglected the hydrodynamic effects on the system. In
general, we would have to take into account flows in the membrane
and the fluid surrounding it, requiring a more involved analysis (see,
e.g., Shlomovitz & Gov (2009) and Frey & Idema (2021)).
For lipid bilayers with up-down symmetry, that is, where both
leaflets have the same lipid composition, the spontaneous curvature
C p is zero. Then, the equilibrium shape that minimizes the bending
energy given by equation (6)—assuming suitable boundary condi-
tions—corresponds to a flat membrane. However, differences in
bilayer composition and—importantly—interactions with proteins
can lead to a non-zero spontaneous curvature (Leibler, 1986;
Lipowsky et al, 1998; Zimmerberg & Kozlov, 2006; Yue et al, 2010;
Sorre et al, 2012; Sodt & Pastor, 2014).
The influence of protein–membrane interactions on membrane
curvature has been studied across scales through numerical simula-
tions (Reynwar et al, 2007; Gov, 2018), experiments (Mim &
Unger, 2012), and through the development of effective field theories
(Weikl et al, 1998; Müller et al, 2005; Haselwandter & Wingreen, 2014;
Haussman & Deserno, 2014; Yolcu et al, 2014; Barakat & Squires,
2022). These works have suggested that proteins are able to impose a
local change of curvature onto a membrane. At the scale of single pro-
teins, this can lead to attractive and repulsive interactions between
proteins due to the curvature of the membrane between them, with a
characteristic length scale defined by the bending rigidity—typically
on the order of 10 nm in cells (Johannes et al, 2018). At larger scales,
be modeled as a spontaneous membrane curvature C p dependent on
the concentration of membrane-interacting proteins: C p ¼ C p ðcÞ
(Leibler, 1986; Bassereau et al, 2014; Argudo et al, 2016; Gov, 2018;
Dymond, 2021). The characteristic length scale of the resulting mem-
brane shape is significantly larger than the length scale of the individ-
ual protein–protein interactions. It depends on the bending rigidity of
the membrane, the induced curvature per protein, and the diffusive
properties of the proteins.
The dependence of the spontaneous curvature on the local pro-
tein concentration leads to a flux term jcurv in the continuity equa-
tion for the protein concentration (equation 1) (Ramaswamy
et al, 2000; Agudo-Canalejo & Golestanian, 2017)
∂t c ¼ Dr2 c þ RðcÞ
r  jcurv : (8)
This term arises from the coupling of protein concentrations to
local membrane shape and depends on the variational derivative of
 2023 The Authors
Jan Rombouts et al EMBO reports

A B C
n n
^ ^

Membrane height h(x,y,t)

R2 Proteins increase
curvature
R1

x R1

R2 Curvature attracts
proteins
x
y
Membrane _( _ _ (
H= 1 1 + 1 _ _( _ _ (
H= 1 1 + 1
Membrane height
Proteins 2 R1 R2 2 R1 R2 Protein concentration

Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.

D E ...
qc = 2π/L 4π/L 6π/L
1
Increasing

C p2
Cp

D
No
Growth rate ω

Instability

qc Control Parameter
10π/L 20π/L 30π/L

Wavenumber q 0
0 24/L
Average Spontaneous Curvature
C p c0

Figure 3. Curvature-mediated pattern formation.

(A) Schematic of a membrane where the shape is described by a height function hðx; y; tÞ. Curvature-inducing proteins are depicted in purple. The proteins can impose a
non-zero spontaneous curvature on the membrane. (B) The mean curvature H is the mean of the two principal curvatures, 1=R1 and 1=R2 , of the membrane at a given
point. The sign convention is chosen such that membranes curving away from the normal of the membrane (red arrow) have a positive curvature, where the normal vec-
tor is defined as positive when pointing out of the cytosolic volume. (C) Schematic of patterning mechanism for curvature-mediated pattern formation. Membrane bend-
ing resistance and protein diffusion are counteracted by a positive feedback loop where high protein concentrations increase the local membrane curvature, which in
turn attracts more proteins to the region. (D) Sketch of the dispersion relation derived from equations (9a) and (9b), relating the growth rate ω to wavenumber q, for a
system of size L. The uniform state is unstable against perturbations with wavenumbers that have positive ω. The critical wavenumber qc corresponds to the highest
wavenumber for which the uniform state is unstable (black dot). The gray dashed and dotted lines indicate how the dispersion relation changes upon changes in Cp . (E)
Stability diagram for curvature-induced patterning on a domain of size L with periodic boundary conditions. The dimensionless control parameter Dτ2 , which indicates the
CP
relative strength of diffusive transport compared with curvature-driven transport, is plotted against the average spontaneous curvature Cp c0 . Contours for the critical wave-
number, qc , are plotted in black. To the left of the line corresponding to qc ¼ 2πL , the uniform state is stable. To the right of the line corresponding to qc ¼ 2πL , the q ¼ 2πL mode
becomes unstable, to the right of the qc ¼ 4πL line both the q ¼ 2πL and q ¼ 4πL modes are unstable, etc.

the free energy with respect to the protein distribution:
jcurv /
rðδF=δcÞ (Mahapatra et al, 2021).
The coupling between curvature and protein distribution can
lead to the emergence of patterns. The conditions for pattern forma-
tion in the coupled system given by equations (7) and (8), with the
free energy given by equation (6), can be obtained by linear stability
analysis (see Box 1). To see how the concentration-dependent
spontaneous curvature by itself can drive patterning, we consider a
system without chemical reactions, that is, R ¼ 0 (Agudo-Canalejo
& Golestanian, 2017), and with a linear dependence of the spontane-
ous curvature on protein concentration C p ðcðxÞÞ ¼ C p cðxÞ, where C p
is positive. An increase in protein concentration thus induces an
increase in spontaneous curvature, which affects membrane shape,
which in turn affects the protein distribution.

 2023 The Authors EMBO reports 24: e57739 | 2023 9 of 24

EMBO reports
The equations for the steady state are solved by a uniform pro-
tein concentration c0 and a corresponding flat equilibrium shape h0 .
Linearizing around this steady state in the small gradient limit—
corresponding to weak bending of the membrane—results in the
equations for small perturbations c~ðxÞ and h~ðxÞ:
2
!
κC p c20 2 ~   protein patterns (Ramaswamy et al, 2000; Tozzi et al, 2019). Mem-
α∂t h~ ¼
κr4 þ r h
κC p r2 c~; (9a)
2 brane tension, in particular, acts in opposition to increases in

  
2 ~
τ∂t c~ ¼ τD þ C p r2 c~ þ C p r4 h: (9b)
Here, τ is a timescale dependent on friction, and inversely propor-
tional to the bending rigidity. The last term in each of these equa-
tions describes the protein–membrane feedback loop, whose
strength depends on the spontaneous curvature induced per pro-
tein in the membrane, C p . From these equations, we can get an
understanding of the curvature-patterning mechanism (see Fig 3C).
The first term on the right side of equation (9a) accounts for the
membrane’s resistance to bending. The cross-term accounts for an
increase in membrane curvature caused by the curvature-inducing
proteins. The first term on the right of equation (9b) is a diffusion
term that spreads the distribution of proteins. This is countered by
the cross-term which attracts proteins to regions of high positive
curvature. Together, these two coupled equations describe a posi-
tive feedback loop that drives pattern formation.
From the linearized equations, we obtain the dispersion relation
(Fig 3D). This shows that modes with wavenumber lower than the
qffiffiffiffiffiffiffiffiffiffiffiffiffi2ffi
Cp
critical wavenumber qc ¼ C p c0 12 þ 2τD are unstable. For a mem-
brane of infinite size, the wavenumbers may take any value. How-
ever, for systems of finite size L with periodic boundaries, the
wavenumbers are constrained to integer multiples of 2π L . This implies
that for finite-sized systems there is no patterning if qc < 2π
L (Fig 3E).
The size of the domain thus determines whether a pattern can form.
The critical wavenumber increases with C p : stronger coupling leads
to more modes becoming unstable (Fig 3D). The wavenumber with
the maximum growth rate, which dominates at the onset of the
instability, also increases monotonically with C p . A similar analysis
can be done for a closed near-spherical geometry such as the surface
of a cell (Agudo-Canalejo & Golestanian, 2017). Although the model
discussed here is too simplistic to be directly applicable in biological
systems, similar mechanisms have been proposed for the distribu-
tion of mechanosensitive Piezo1 ion channels (Yang et al, 2022),
and curvature-sensing proteins have been shown to play a role in
vivo in neuronal cell migration (Guerrier et al, 2009) and immuno-
logical cell function (Koduru et al, 2010).
Models similar to the one described above have also been studied
in different geometries, for example, to explain the regular patterning
of FtsZ proteins in bacteria (Shlomovitz & Gov, 2009) and, when
coupled to active forces, to explain the formation of membrane
waves (Shlomovitz & Gov, 2007; Peleg et al, 2011; Gov, 2018).
In summary, whereas purely chemical systems need multiple
components for pattern formation (see section “Introduction”), a
single species of diffusing molecules can lead to pattern formation
when coupled to membrane mechanics. In the example we have
discussed, the local curvature induced by a protein reduces the
membrane bending energy associated with other proteins close by.
10 of 24 EMBO reports 24: e57739 | 2023
Jan Rombouts et al
Thus, an increase in local curvature will lead to an increase in the
flux of curvature-inducing proteins into the region, providing a posi-
tive feedback loop that clusters curvature-inducing proteins, accom-
panied by a further increase in the local curvature. Further
constraints on the membrane, such as incompressible enclosed vol-
umes, may play a role in mode selection and the formation of stable
membrane curvature and provides a biophysical means to tune the
wavelength of emergent patterns (Agudo-Canalejo & Golesta-
nian, 2017). Many of the results discussed in this section are valid
in the limit of small membrane deformations, and it remains an
interesting problem for future research to model curvature-mediated
patterning in the large deformation limit (see Box 2).
In the biological context, curvature-coupled proteins do not oper-
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
ate in isolation. Commonly, curvature-sensing proteins comprise
part of larger biochemical networks. In such systems, curvature cou-
pling may provide additional feedback loops and give rise to
rich patterning dynamics. For example, the inclusion of membrane–
curvature coupled interactions has been suggested to enhance the
robustness of biochemical pattern formation against stochastic fluc-
tuations (Liu et al, 2009). Therefore, curvature-driven patterns not
only allow for cells to break symmetry and develop structural pat-
terns but may also protect these patterns from environmental and
system variability (Cail & Drubin, 2023). Moreover, in most cellular
contexts, the plasma membrane is coupled to adjacent cytoskeletal
components, which typically dominate the shape dynamics on
length scales of 1-10 µm. In animal cells, a meshwork of actin fila-
ments crosslinked by various proteins, including myosin motors,
forms beneath the plasma membrane and controls cellular shape
changes associated with, for example, migration and division
(Kelkar et al, 2020). Many of these essential cellular processes can
be explained by considering pattern formation within the cell cortex,
which we discuss in the following section.
Contractile fluid patterning
Many living systems can generate active stresses at mesoscopic
scales from microscopic processes that consume ATP or other fuel
molecules. The myosin motors in the actin cytoskeleton, for exam-
ple, transduce metabolic energy into work by stepping along or
moving the filaments they are bound to. The activity of such motors
gives rise to large-scale and typically contractile active stresses
within the material.
Contractile active stresses in combination with self-induced con-
vective flows give rise to a paradigmatic patterning mechanism, the
contractile instability (Bois et al, 2011; Kumar et al, 2014; Hannezo
et al, 2015; Palmquist et al, 2022). The intuitive idea underlying the
instability is as follows: an active generator of mechanical stress,
such as myosin, induces local contraction of the material, which
produces a flow toward the region of contraction, bringing in more
of the regulator and increasing the contraction further. This positive
feedback loop can lead to regularly spaced regions of high contrac-
tility with associated flows toward them (Fig 4A).
Contractile instabilities appear in the cell cortex, where the cell
itself is the domain on which the pattern forms and the contractile
units are molecules. However, a cell can also be one of the small
 2023 The Authors
Jan Rombouts et al EMBO reports

units that contribute to a larger, tissue-scale pattern. Adherent cells
typically exert active contractile stresses on their environment
(Schwarz et al, 2002; Schwarz & Safran, 2013; Tanimoto &
Sano, 2014). Similar to the way in which myosin molecules inside
the actin network act as contractile elements, the cells themselves
can constitute contractile units within a meshwork of extracellular
matrix (ECM) filaments. As such, they can induce active rearrange-
ments of the cell–ECM system, leading to contractile patterning at
the multicellular level (Fig 4B, Harris et al, 1984; Shyer et al, 2017;
Palmquist et al, 2022). Systems consisting of contractile cells
embedded in extracellular matrix were, in fact, one of the earliest
systems where mechanical forces were studied as a biological
pattern-forming mechanism (Oster et al, 1983; Harris et al, 1984).
To study contractile patterning theoretically, we write the conti-
nuity equation (equation 1) for the concentration of contractile par-
αv ¼ ∂x σ; (11)
where the left-hand side corresponds to an external frictional stress
with friction coefficient α as before. For a contractile Newtonian
fluid, the stress consists of two parts: σ ¼ η∂x v þ σ A . Here, η is the
viscosity, and the active stress σ A ðcÞ depends on the concentration
of the regulator. For contractile regulators, an increase in c leads to
an increase in stress. Many studies assume a saturating relation
between the active stress and the concentration of contractile
particles (e.g., Bois et al, 2011; Mietke et al, 2019b). However, in
the simplest case, valid for low concentrations, each unit (e.g.,
myosin molecule or contractile cell) imparts the same average
stress σ A to the material. Then, the active stress contribution
depends linearly on the concentration of contractile particles,
which we write relative to the average concentration c0 :

Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.

ticles c in one dimension: σ A ðcÞ ¼ σ A c=c0 .
In the absence of chemical reactions or turnover—RðcÞ ¼ 0—,
∂t c ¼ D∂xx c
∂x ðvcÞ þ RðcÞ; (10) the total amount of regulator is conserved (Bois et al, 2011; Palm-
quist et al, 2022). At steady state, the concentration is uniform at c0 ,
and include diffusive and convective fluxes and a reaction term. and there are no flows: v0 ¼ 0. Linear stability analysis of this
The velocity v is determined by the force balance equation (equa- steady state reveals that the growth rate ω of a spatial mode with
tion 3): wavenumber q obeys the following dispersion relation:

A high active stress C Growth rate Re( ) Dominant wavenumber qmax

A

contractile elements 20/R

convective flow 0
10/R

B 0
0 10/R 20/R 30/R 0 10 20
20 min
Perturbation wavenumber q Péclet number

D 150
1 μm
Péclet number

100 Unstable
20 h

50
Stable

0
1000 μm 0 0.25 0.5 0.75 1
Hydrodynamic length Lh/R

Figure 4. Contractile fluid patterning.

(A) Particles generating an active contractile stress σ A within a viscous environment drive spontaneous patterning by inducing convective flows into regions of large
concentration. (B) Contractile patterning occurs across spatial scales and levels of biological organization. Top: Myosin motor proteins aggregate within the actin
cytoskeleton, for example, in the cytokinetic rings of fission yeast (adapted from Wollrab et al, 2016). Bottom: At much larger spatial scales, cells themselves can act as
contractile elements within extracellular filament networks, leading to, for example, patterning of mesenchymal fibroblasts in collagen (adapted from Palmquist
et al, 2022). Schematics represent the respective contractile units. (C) Linear stability analysis of a one-dimensional contractile system on a ring with radius R reveals
how the dominant modes at the onset of instability depend on the Peclet number, the ratio between convective and diffusive timescales (adapted from Palmquist
et al, 2022). Dispersion relations are shown for three different Peclet numbers (left). The wavenumber with maximal growth rate increases as a function of Peclet number
(right). (D) On a spherical domain with radius R, the ratio of the hydrodynamic length Lh to the system size R determines the symmetry of the most unstable mode. This
leads to distributions of contractile elements reminiscent of migrating cells for large Lh (gray instability line) or dividing cells for smaller Lh (blue instability line; adapted
from Mietke et al, 2019a).

 2023 The Authors EMBO reports 24: e57739 | 2023 11 of 24

EMBO reports
!
σA
ω ¼
Dq2 1
αD
: (12)
1 þ αη q2
The equation reveals that the existence of an instability only
depends on two quantities. The ratio σ A =ðαDÞ is called the Peclet
number and indicates the relative strength of the advective trans-
pffiffiffiffiffiffiffiffi
port compared with the diffusive transport. The ratio η=α is a
length scale characterizing the spatial range of flows called the
hydrodynamic length. There are solutions ω > 0, corresponding to
the emergence of patterns, only when the Peclet number is larger
than 1 (Fig 4C). This shows that patterns form if the hydrodynamic
flow induced by active stress is strong enough to overcome the sta-
bilizing effect of random diffusive motion.
The fundamental pattern-forming process is a self-amplifying
feedback loop where more regulator means more inward flow,
bringing in even more regulators. This becomes clearer when writ-
ing the equation in the low-viscosity limit, η ! 0:
σA
∂t c ¼ D∂xx c
∂x ðc∂x cÞ:
c0 α
The local concentration evolves according to diffusion, the first
term, which acts to smooth out concentration differences. The sec-
ond term here describes that molecules move up their own gradi-
ent—the self-amplifying feedback loop. If the latter outweighs
diffusion, an instability appears. This mechanism, and the equa-
tions to describe it, are similar to pattern formation in chemotaxis
and so-called Keller–Segel models. In the case of chemotactic bac-
teria, the feedback loop is as follows: bacteria locally produce
chemoattractant, bringing in more bacteria, producing more
chemoattractant, and so forth. Again, this competes with the stabi-
lizing effect of random motion—in this case of the organisms.
Instabilities of this type occur across diverse biological contexts
(see Painter, 2019, for a review).
In particular, the contractile fluid instability has been proposed
to govern the arrangement of the feather follicles on the skin of
birds (Shyer et al, 2017; Palmquist et al, 2022). The corresponding
pattern-forming system can be reconstituted ex vivo on a quasi-
one-dimensional ring domain: when plated in drops on a collagen
substrate, the dissociated dermal cells from chick embryos settle
on the boundary of the droplet and undergo spontaneous pattern-
ing (Fig 4B). Over the course of aggregation, the cell–ECM layer in
this system undergoes irreversible remodeling. The cells enmesh
themselves, remodel, and induce irreversible rearrangements in
the surrounding collagen, giving rise to an effective fluid-like
behavior of the cell–ECM layer on the timescale relevant for pat-
tern formation (1–10 h). Pharmacological perturbations to the
Peclet number and the hydrodynamic length yield changes in the
number of aggregates and the timescale of patterning that are in
good quantitative agreement with the predictions of the dispersion
relation (equation 12). Increasing cellular contractility leads to
faster patterning and more aggregates, and increasing hydrody-
namic length leads to slower patterning into fewer aggregates
(Palmquist et al, 2022). In this system, the final patterns are well
described by linear stability analysis because the structures that
appear immediately after the onset of the instability are stabilized
by other mechanisms. In vivo, density differences are read out at
early stages by beta-catenin signaling (Shyer et al, 2017), while ex
12 of 24 EMBO reports 24: e57739 | 2023
Jan Rombouts et al
vivo, the depletion of material in between aggregates eventually
appears to prevent sustained flows.
Another experimental system in which a contractile instability
has been studied is the Drosophila tracheal tube. For this system,
Hannezo et al (2015) included a reaction term of the form
RðcÞ ¼ ðc0
cÞ=τ to describe turnover at a timescale τ. The linear
stability analysis shows that here too, patterns emerge when advec-
tion dominates over other effects. Like diffusion, the turnover coun-
teracts the self-amplifying feedback loop of accumulation. Genetic
and pharmacological perturbations to actin patterns in these cells
also yield wavelength changes that match theoretical predictions.
Kumar et al (2014) extended the framework of contractile insta-
bilities to two chemical species. One species upregulates the active
stress and another downregulates it. In addition to stationary pat-
terns, such a system also shows an oscillatory instability which
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
leads to pulsating flow patterns. These pulsating patterns appear if
the diffusion constants or the relaxation timescales for the upregu-
lating and downregulating species are different.
Depending on the form of the reaction term, irregular spatiotem-
poral behavior is also possible. This has been described in the
Keller–Segel model (Painter & Hillen, 2011): the inclusion of a qua-
dratic growth term can lead to spatiotemporal patterns, with the
irregular appearance and disappearance of high-density regions.
Hannezo et al (2015) also observed this in an extension of the
model for actin dynamics in Drosophila tracheal cells, and linked it
to the dynamic behavior of actin rings they found in one of the fly
mutants.
Both the inclusion of multiple species and the addition of reac-
tion terms can thus modify the patterns generated by contractile
instabilities. On the other hand, patterns that are generated due to
purely chemical interactions may be modified if the chemical spe-
cies also induce flows. For example, if an activating chemical in a
reaction–diffusion system also induces flows, the region in parame-
ter space where patterns can be found become larger (Bois
et al, 2011).
Contractile instabilities have been linked to the polarization of
the cell cortex during cell migration, in particular where cells
migrate without focal adhesions (Hawkins et al, 2011; Bergert
et al, 2015; Liu et al, 2015; Ruprecht et al, 2015). For example, Haw-
kins et al (2011) study how contractile instabilities in the cortex of a
spherical cell can lead to the spontaneous movement of the cell.
Their model considers both actin and myosin concentrations in the
cortex, recruitment of myosin from the cytoplasm, and the velocity
field of the cortex. As in the study by Bois et al (2011), a linear sta-
bility analysis reveals that a contractile instability happens if the
Peclet number is sufficiently large. An important difference is that
the analysis is done on a spherical domain, rather than a one-
dimensional one. On a sphere, the pattern is characterized by unsta-
ble modes in the form of spherical harmonics (Figs 4D and 1C). In
the model by Hawkins et al (2011), the most unstable mode at the
onset of instability produces a polarized state where flows at the cell
surface converge from one pole toward the opposite. The frictional
coupling to the surroundings permits these active surface flows to
generate a propulsion force that moves the cell forward. Indeed,
migrating cells in many contexts exhibit gradients of myosin along
their axis of motility, accompanied by rearward surface flows that
drive propulsion in a friction-dependent manner. The above formal-
ism accurately and quantitatively predicts surface flows and cell
 2023 The Authors
Jan Rombouts et al
velocities of migrating tumor (Hawkins et al, 2011; Bergert
et al, 2015), immune (Liu et al, 2015), and embryonic progenitor
cells (Ruprecht et al, 2015).
The dimension and shape of the domain on which the actin cor-
tex is modeled are important for the resulting pattern, by
constraining the spatial modes that can become unstable (see also
Box 1, Fig 1C and section “Geometry-dependent reaction-diffusion
patterns”). In real biological systems, contractile stresses can lead to
deformations of this shape. Some studies have addressed how non-
uniform contractile stresses and flows change the system’s shape
(Ruprecht et al, 2015; Callan-Jones et al, 2016), and how this in turn
may feed back onto the flow pattern (Mietke et al, 2019a, 2019b).
Ruprecht et al (2015) and Callan-Jones et al (2016) study shape
deformations due to cortical flows. As in the paper by Hawkins
et al (2011), these studies were inspired by cell migration in three
dimensions. The authors show that patterned active stress can pro-
duce an elongated cell shape, which corresponds to experimental
observations.
The pattern of flow and contraction can thus lead to shape
changes, but these, in turn, may influence the dynamics of surface
concentrations. Mietke et al (2019b) studied the time evolution of
coupled velocity and concentration fields on changing domains. The
model equations describe the evolution of the concentration of a
regulator of contractility and of the surface itself. The regulator is
subject to advection and diffusion, which are influenced by the
changing surface shape. The authors analyze the equations using
linear stability analysis and numerical simulations and focus on (ini-
tially) spherical and tubular domains. On the spherical surface,
instability can lead to polarization with high concentrations on one
side, with a concomitant shape change. On the tubular domain, the
instability can induce constriction of the tube with flow toward
the narrow middle part. Moreover, oscillations and peristaltic waves
are also possible. In a follow-up work, Mietke et al (2019a) extend
the formalism and couple the active surface to a bulk fluid in order
to capture the interaction between the actomyosin cortex and the
cytoplasm of a cell. Here, the contractile instability is accompanied
by flows in the bulk, too. If the hydrodynamic length is small, the
first mode to become unstable has a symmetric flow pattern with a
ring of high concentration of regulator in the middle (Fig 4D), remi-
niscent of the contractile cytokinetic ring in dividing cells.
In summary, the physical principles of patterning through a con-
tractile fluid instability apply across spatial and temporal
scales spanning three orders of magnitude. Their theoretical analysis
unveils connections between different levels of biological organiza-
tion. Moreover, these works on contractile instability demonstrate
how living systems can inspire new theoretical developments. The
force-generating, energy-consuming properties of the actomyosin
cortex, coupled with the cell’s geometry, provide a system that does
not have analogies in more traditional physical contexts.
Buckling due to constrained growth
Contractile instabilities are characterized by self-amplifying local-
ized contractions. Another mechanism that can lead to mechanical
instability—buckling—does not require localized contractility but
can be generated by global growth or compression. Buckling is a
familiar phenomenon from the everyday world, which arises if
 2023 The Authors
EMBO reports
a thin object is subject to compressive forces, which lead to its bend-
ing. Buckling instabilities are also relevant for pattern formation in
biological systems, where they can lead to regular wrinkles or folds.
The formation of folds is important in many systems, including the
gut (Savin et al, 2011; Shyer et al, 2013), the wrinkles of the brain
(Llinares-Benadero & Borrell, 2019), the development of the Dro-
sophila wing (Tozluoğlu et al, 2019), and others (see Nelson, 2016,
for a review). Buckling due to differential growth is a key mecha-
nism in the determination of leaf shapes (reviewed in Guo
et al, 2022). We do not discuss this in this review, but mechanical
forces in general play an important role in plant morphogenesis (see
Sampathkumar, 2020, for a review).
Other mechanisms besides buckling, such as localized contrac-
tion or non-uniform growth, can also lead to folding (see Tozluoğlu
& Mao, 2020, for an overview). In biological systems, it is not easy
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
to distinguish which of these mechanisms is responsible for folding,
even more so because they may act together. Recent advances have
been made by Trushko et al (2020) in an in vitro system. There, the
authors encapsulate a cell monolayer in an elastic alginate capsule.
The growth of the monolayer leads to its folding. The folding did
not occur in the absence of cell proliferation or of the encapsulating
shell, pointing to buckling as the main folding mechanism. The
setup also allows the measurement of material properties of the tis-
sue, which the authors compared with continuum theory.
The buckling of beams and sheets is a classic problem in physics,
but its application to biological systems has brought new elements to
the theory. Rather than externally applied compressive stresses, in bio-
logical systems, it is often the growth of the tissue under confinement,
or differential growth, that can lead to instability. The confinement
can, for example, be due to a shell or surrounding tissues.
There is a wide range of literature on the mathematical descrip-
tion of growing systems (see Goriely, 2017; Ambrosi et al, 2019).
Here, we will not go into the continuum mechanics of growing sys-
tems, but provide a simplified example based on energy consider-
ations to show how buckling-type instabilities can lead to pattern
formation in constrained growing systems.
We illustrate the appearance of a buckling instability using a
model for an epithelial monolayer attached to an elastic substrate
with uniform cell growth (Fig 5A; inspired by Hannezo et al (2011)
and Hannezo et al (2012), see also Brangwynne et al (2006) for a
similar treatment of microtubule buckling). We assume a one-
dimensional system, where the height of the epithelium is given by
h. In the weak bending approximation, also used in the section “Pat-
tern formation by membrane curvature” for the cell membrane, the
energy of the epithelium is given by
Z L   
1 1 β
F¼ κð∂xx hÞ2 þ γ 1 þ ð∂x hÞ2 þ ðh
h0 Þ2 dx: (13)
0 2 2 2
The first term is the bending energy, which is the same as for the
discussion on biological membranes in the section “Pattern forma-
tion by membrane curvature”. The second term models the
growth of the tissue, and can in this equation also be interpreted
as a surface tension: the effect of cell proliferation is to locally
increase the area—which can be modeled by considering a nega-
tive surface tension γ < 0. The final term is the energy needed to
deform the substrate. The parameter β is related to the substrate’s
stiffness and h0 is a reference height. For simplicity, we consider
EMBO reports 24: e57739 | 2023 13 of 24
EMBO reports Jan Rombouts et al

A B

C D E

Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.

F G H

Figure 5. Buckling and waves.

(A) Cell growth in an epithelium attached to a substrate can lead to its buckling. (B) Bacterial biofilms that grow on a substrate can develop wrinkles due to a buckling
instability (see also Fig 1A). (C) In epithelial sheets of MDCK cells, ERK waves propagate in the opposite direction of collective cell motion. (D) A negative feedback loop
between cell length and ERK activity can lead to the emergence of mechanochemical waves in epithelial monolayers. (E) Dispersion relation for equation (15). For low
feedback strength ab, the steady state is stable. Higher values of ab lead to an instability. The growth rate has an imaginary part, which corresponds to traveling wave
patterns. The waves’ spatial and temporal frequency are determined by qmax and Imðωmax Þ, respectively. Adapted from Boocock et al (2021). (F) Metachronal waves in
ciliary arrays. Beating cilia generate flow fields. The fluid flows couple the motion of nearby cilia, which can give rise to coordinated motion and waves with a
characteristic wavelength λ. (G) Synchronization of cilia and the emergence of metachronal waves can be modeled using coupled oscillator models. Each oscillator i is
represented by its phase φi , a number between 0 and 2π. The coupling strength can depend on the distance between the oscillators. If there are many oscillators, a
continuum model can be appropriate, where the phase φ is a smooth function of position x (bottom). (H) The flow field generated by ciliary beating can be
approximated by that of a sphere following an orbit above a plane. The distance of the sphere to the plane d determines the spatial decay of the generated flow field
and therefore the form of the coupling function.

only elastic penalties to changes in the height. As before, one can
do an analysis of the stability of a flat epithelial layer, which
shows that a pattern-forming instability is possible when the
growth of the layer overcomes the resistance to bending and the
resistance to deformation of the substrate. The wavelength of the
pattern depends on the mechanical properties of the tissues
involved (Brau et al, 2013). The equation above is a simplified
illustration; for an overview of different modeling approaches to
this problem, see the paper by Almet et al (2020) and references
therein.
Buckling instabilities may be followed by changes in signaling,
as has been shown for example in the formation of villi in chick
embryos (Shyer et al, 2015). There, the curved geometry induced by
the folding leads to a patterned distribution of morphogens, which
impacts the localization of stem cells in this system. There is thus
an interplay among mechanics, geometry, and signaling.

14 of 24 EMBO reports 24: e57739 | 2023  2023 The Authors

Jan Rombouts et al
Buckling due to constrained growth is not only seen in epithelial
tissues but also in multicellular systems of another kind: bacterial
biofilms. While a biofilm’s size increases by the division and growth
of bacteria, its substrate does not grow. This leads to the accumula-
tion of stresses that result in a buckling instability and the appear-
ance of wrinkles in the biofilm (Figs 5B and 1A). In a study by Yan
et al (2019), these wrinkles develop into a striking star-like pattern
with a well-defined wavelength. Classical theory for film–substrate
systems predicts that the wrinkle wavelength should scale as
ðGf =Gs Þ1=3 , where Gf and Gs are the shear moduli of biofilm and sub-
strate. These moduli, which characterize a material’s response to
shear stresses, can be measured using a shear rheometer. The scal-
ing relation is seen to hold true in a range of stiffnesses, but the
two-layer model is not an accurate description of the data for small
Gf . Yan et al (2019) show that a model including a third layer is a
better description of the data.
In bacterial biofilms, there can also be feedback between
mechanics and biochemistry. Based on the pattern formation
observed by Yan et al (2019), Fei et al (2020) set up a model of bio-
film growth that also includes nutrient uptake and diffusion. Here,
variations in nutrient concentration lead to inhomogeneous growth
profiles, which influence the appearance of wrinkles. This system is
another example of interactions among biochemistry, mechanics,
and shape. The shape of the biofilm influences where nutrient
uptake is highest, and nutrient availability determines the local
growth rate, which then guides the shape of the biofilm.
Biofilms have recently been used to study other aspects of pat-
tern formation in which mechanics plays a role. For example,
mechanical instabilities are at the origin of verticalization and radial
alignment, producing long range order in biofilms (Beroz
et al, 2018; Nijjer et al, 2021).
The two examples of this section, epithelia and biofilms, illus-
trate how growth under confinement can lead to periodic patterning.
Here, the patterning instability generates the tissue’s or biofilm’s
shape. In turn, the shape can affect further mechanical or biochemi-
cal processes. These systems are another illustration of how
mechanics and shape can introduce feedback loops that lead to the
emergence of spatial patterns.
Waves through mechanosensing
In the preceding sections, we mainly discussed mechanochemical
systems in which feedback arises directly due to geometrical or
mechanical effects on the distribution of constituents, such as
curvature-dependent localization (section “Pattern formation by
membrane curvature”) or convective flows (section “Contractile
fluid patterning”). At the multicellular level, however, the capacity
of cells to sense mechanical properties and forces through special
mechanosensory machineries and signaling pathways can become
relevant for pattern formation. Mechanical forces sensed by the cell
can lead, among others, to changes in gene expression, subcellular
localization, or post-translational modifications of proteins. In turn,
these biochemical changes can affect the mechanical properties of a
cell. In this way, mechanosensors can be part of mechanochemical
feedback loops. Mechanosensing and mechanotransduction are
important processes, but a more detailed discussion lies outside the
scope of the current paper. We refer to the reviews by Chan
 2023 The Authors
EMBO reports
et al (2017), Petridou et al (2017), and Kindberg et al (2020), and
references therein, for more information.
In this section, we discuss one particular example where the ability
of cells to respond to mechanical changes gives rise to pattern forma-
tion, involving an interplay between extracellular signal-regulated
kinase (ERK) activity and cellular shape. The pattern discussed in this
section is varying not only in space but also in time, in the form of
waves. Waves of ERK activity and contractility appear in systems
of collectively moving cells (Aoki et al, 2017; Hino et al, 2020;
Boocock et al, 2021). Collective cell motion is important for many bio-
logical processes in the development and maintenance of an organ-
ism, and a wide range of physical modeling approaches exists (see
Alert & Trepat, 2020, for a review). Collectives of moving cells in epi-
thelia show varied dynamics, including oscillatory motion and the
propagation of mechanical waves (see, e.g., Dierkes et al, 2014;
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
Zaritsky et al, 2014; Banerjee et al, 2015; Blanch-Mercader & Casade-
munt, 2017; Peyret et al, 2019, and references therein). In sheets of
epithelial migrating Madin–Darby canine kidney (MDCK) cells, waves
of ERK activity propagate against the direction of the cell motion (Aoki
et al, 2017; Figs 5C and 1A). These waves also appear in non-
migrating sheets of cells, where they are generated spontaneously in
random directions (Boocock et al, 2021), and have been observed
in vivo in mouse skin (Hiratsuka et al, 2015).
The protein kinase ERK is involved in different cellular path-
ways. Its role in collective motion has recently been addressed using
FRET sensors detecting the activity of the protein (Aoki et al, 2017;
Hino et al, 2020). Live imaging of moving cells and traction-force
microscopy have been combined with mathematical modeling to
uncover how forces, motion, and signaling work together. In paral-
lel with the increasing availability of spatiotemporal data, theoreti-
cal models of the system have been refined. The development of a
simple continuum model by Boocock et al (2021), based on detailed
experiments by Hino et al (2020), has elucidated how the interaction
between signaling and cell contraction can lead to the appearance of
spontaneous waves as well as organized collective motion.
The model describes an epithelial monolayer of cells as a one-
dimensional chain of overdamped springs. Using force balance,
Boocock et al (2021) derive a continuum equation for the displace-
ment of the cells:
τr ∂t r ¼ ∂xx r
∂x ‘0 ; (14)
in which spatial scales have been normalized to the reference
length of an individual cell. The time scale τr depends on the fric-
tion of the cells with the substrate and the strength of the spring-
like coupling.
The equation for r is complemented by one for the preferred cell
length, ‘0 and a third variable E that represents the local ERK activ-
ity. Hino et al (2020) found that ERK activity induces cell contrac-
tion. This can be modeled by stating that ERK levels tend to
decrease ‘0 . Experiments have also shown that cell extension
induces an increase in ERK levels, indicating that a mechanosensory
process gives rise to feedback between the cell’s mechanical and
biochemical states (Fig 5D). However, how exactly the mechanical
changes lead to a change in ERK activity is not fully understood
(Hirashima et al, 2023). How this feedback is implemented thus
becomes a modeling choice: Is ERK activation induced by absolute
cell size, the cell strain, or strain rate? Boocock et al (2021), in an
EMBO reports 24: e57739 | 2023 15 of 24
EMBO reports
extended discussion of the model’s assumptions, show that only the
first choice leads to patterns in the model. This could provide a the-
oretical pointer toward the biological mechanism.
The equations for the model, with preferred cell length and ERK
levels rewritten as a deviation from a basal level, are given by
τr ∂t r ¼ ∂xx r
∂x ‘0 ;
τ‘ ∂t ‘0 ¼
‘0
aE; (15)
τE ∂t E ¼
E þ b∂x r:
The three constants τr ; τ‘ and τE are the timescales of evolution of
the three variables. They are, like the Peclet number in the section
“Contractile fluid patterning”, combinations of physical parameters
such as friction constants and elastic coefficients. Importantly,
these timescales correspond to directly measurable quantities: if
one of the variables is perturbed from a steady state, the value of
the corresponding τ indicates the timescale on which it relaxes
back to that state. For example, an estimate for τE can be obtained
by fitting an exponential function to measured ERK activity after
mechanical stretching (Hino et al, 2020). The term
aE indicates
that ERK activity induces contraction, and b∂x r describes how cell
extension induces ERK activation. This model does not contain
detailed information about how ERK activity may biochemically
induce cell contraction, nor how extension may lead to a rise in
ERK levels. However, this information is not needed to make pre-
dictions about the large-scale behavior of the system. All of the
biochemistry is summarized in the parameters a and b. What is
important is their sign, and their absolute value gives an indication
of the strength of the feedback.
A linear stability analysis of the system reveals that the exis-
tence of an instability, and thus patterns, depends on the value
of ab; the product of the feedback strengths (Fig 5E). In contrast
to the instability that results in stationary patterns, the growth
rate ω now has an imaginary component. The unstable mode is
thus oscillatory in time and space, which indicates that the sys-
tem supports traveling waves. The imaginary part of ω deter-
mines the temporal frequency of the waves. The oscillatory
behavior is due to the negative feedback loop that is inherent in
this system, even on a local level (Fig 5D): a cell’s extension
leads to ERK activation, which leads to a smaller preferred cell
length, which leads to contraction, etc. Negative feedback loops
are well-known to generate oscillatory behavior, and combined
with spatial coupling, they can lead to the appearance of traveling
waves (Beta & Kruse, 2017).
Further analysis of the dispersion relation shows that the spatial
wavelength and the temporal frequency of the waves close to the
instability only depend on the three different timescales. Indepen-
dent measurements of these timescales can thus be used to predict
wavelength and frequency. The measurements for these timescales
predict values of the wavelength and frequency in the range of the
experimental observations. This correspondence between theory
and experiment supports that the proposed wave-generating mecha-
nism is a plausible one.
The waves that are predicted by this theory have no preferred
orientation: they can be induced by noise in the system and prop-
agate in random directions. This recapitulates the observed ran-
dom propagation of ERK waves in non-migrating sheets of MDCK
cells.
16 of 24 EMBO reports 24: e57739 | 2023
Jan Rombouts et al
The directed propagation of ERK waves, which corresponds to cell
migration in the direction opposite to the waves, can be explained by
coupling the ERK–cell extension dynamics to cell polarity. Boocock
et al (2021) investigate a model where cell polarity is induced by
stress gradients. Cell polarity, in turn, affects the evolution of r. Simu-
lations of this extended model show that the system can indeed pro-
duce collective cell migration. In this model, ERK waves that travel
away from a free edge correspond to a persistent polarization of the
follower cells, thereby guiding them to migrate collectively in the
direction of the edge. Moreover, the model predicts that there is an
optimal wavelength and frequency of ERK waves that produce the
strongest average polarization. The ERK waves that have been
observed in experiments have frequency and wavelength which
roughly correspond to these optimal values, which suggests that the
system is tuned for an optimal migration speed.
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
The ERK waves are an example where mechanics is one of the
elements in a feedback loop that also includes biochemical compo-
nents. Additionally, the patterns in this case vary in space as well as
time, and a linear stability analysis provides information about the
spatial and temporal scale of the patterns. Finally, the theory
worked out by Boocock et al (2021) links the formation of patterns
to a biological function, namely cell migration.
Metachronal waves in arrays of hydrodynamically coupled
oscillators
The mechanochemical waves described in the previous section arise
from the instability of a uniform stationary steady state. However,
waves can also be generated by different mechanisms. In systems
where the individual units are already oscillatory, long-range spatial
patterns in the form of traveling waves can emerge due to coupling
between different oscillators. If the individual units are moving
appendages such as cilia or limbs, these waves are called meta-
chronal waves. They are characterized by a phase shift between
neighboring oscillators, which results in a typical wavelength λ
(Fig 5F). In systems of cyclically moving appendages such as cilia or
flagella, metachronal waves can generate locomotion of small organ-
isms or fluid flows that transport particles (see, e.g., Byron
et al, 2021, for an overview).
Metachronal waves are often studied using the theoretical frame-
work of coupled oscillators. In coupled oscillator models, a compli-
cated oscillating system is described by a single number: its phase
(Fig 5G). As the oscillator traverses its cycle, the phase φ increases
from 0 to 2π. Such models can describe a wide variety of systems—
from the synchronization of flashing fireflies to mechanically
connected metronomes (Pikovsky et al, 2003).
A general model of interacting oscillators reads
d    
φ ¼ ωi þ ∑G jr i
r j j H φi ; φj ; (16)
dt i j
in which φi is the phase of oscillator i, located at position r i
(Fig 5G). Here, ωi is the frequency of the unperturbed oscillator
and the function H describes how the coupling between oscillators
depends on their phases. The function G describes how the
strength of the coupling depends on the distance between
the oscillators.
 2023 The Authors
Jan Rombouts et al
Equation (16) is an equation for discrete oscillators, which is the
form mostly used for studying metachronal waves. Some studies,
however, use continuous phase equations, where the phase is given
by a field φðx; tÞ (Fig 5G, Chakrabarti et al (2022) and Quillen (2023)).
Interestingly, continuous phase equations with non-local coupling
also appear in models of collections of neurons, where long-range
interactions are due to the spatial extent of axons (e.g., Crook et al,
1997). A continuous version of equation (16) reads
Z
∂t φðx; tÞ ¼ ωðxÞ þ dyGðjx
yjÞH ðφðx; tÞ; φðy; tÞÞ: (17)
A uniformly oscillating system is a solution to this equation with
φðx; tÞ ¼ ωt. It is, similar to the examples in the other sections,
possible to do a linear stability analysis of this state. Moreover,
depending on the functions G and H, it is possible to examine ana-
lytically the existence and stability of traveling wave states of the
form φðx; tÞ ¼ qx þ ωt, where q is the wavenumber. Equations like
equation (17) can admit multiple distinct wave solutions, and
which waves are more likely to be seen in systems described by
these mathematical models is an ongoing topic of study (see, e.g.,
Wiley et al, 2006; Solovev & Friedrich, 2022). Moreover, theoretical
studies of non-locally coupled oscillators showed that these models
support other types of behavior, such as the coexistence between
synchronized regions with randomly oscillating oscillators (e.g.,
Kuramoto & Battogtokh, 2002; Abrams & Strogatz, 2004). This
raises the intriguing question of whether real biological systems,
such as ciliary arrays, could also show these kinds of behavior
(see Gilpin et al, 2020, for a more extended discussion).
A prominent biological example of metachronal waves is found
in arrays of cilia. Each cilium is a hair-like appendage that exhibits
periodic motion due to the activity of internal molecular motors
(recent overviews of the physics of cilia and flagella are given by
Wan, 2018; Gilpin et al, 2020). This motion generates a fluid flow
that influences neighboring cilia (Fig 5F). Due to the relatively long-
ranged nature of fluid flows, the interactions between cilia are non-
local. This illustrates how mechanical features can lead to types of
coupling that are different from the coupling produced by, for exam-
ple, diffusion, or local mechanical coupling such as in epithelial
tissues.
Understanding the physics of metachronal waves on ciliary
arrays is a multiscale problem from the molecular to the organismal
scale (Chakrabarti et al, 2022). General scaling arguments from
hydrodynamics, however, can provide insights into the spatial inter-
actions between cilia because the flow field at a certain distance
from the cilium can be well approximated by the flow field of a
sphere moving on a cyclic orbit (Brumley et al, 2014; Fig 5H). Flow
fields decay with distance r as 1=r for free spheres and as 1=r 3 for
spheres close to a wall (e.g., Happel & Brenner, 1983; Vilfan & Jüli-
cher, 2006; Niedermayer et al, 2008), implying a similar scaling for
the coupling between oscillators. These hydrodynamic arguments
provide the basis for some of the coupled oscillator models (Fig 5G),
in which the hydrodynamic effects between the cilia determine
the functions G and H in equation (16). For example, Uchida &
Golestanian (2010) apply multiple approximations to a hydrody-
namic model and derive a reduced model with Gðr Þ ¼ A=r 3 and
   
H φi ; φj ¼ sin φj
φi þ δ , in which the coupling strength A
depends on properties of the fluid surrounding the cilia.
 2023 The Authors
EMBO reports
Importantly, the range of spatial coupling determines the stability of
metachronal waves (Wollin & Stark, 2011; Brumley et al, 2016).
The mechanical aspect relevant to metachronal waves is mainly
the hydrodynamic coupling. However, the shape of the domain on
which the ciliary arrays are present can also be important. In the
natural world, ciliary arrays often appear on non-flat domains such
as spheres. The question of how different domain shapes affect the
synchronization of coupled cilia has recently been addressed theo-
retically (e.g., Westwood & Keaveny, 2021, and references therein).
Ciliary arrays are not the only biological systems that show meta-
chronal waves. They also appear on the level of multiple organisms,
as has been described by Peshkov et al (2022). In this study, the
authors observe swimming nematodes (T. aceti or vinegar eels, see
also Fig 1A). These small worms, when confined in liquid droplets,
synchronize their undulating motion when their density is high. The
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
authors also describe a model based on coupled oscillators (Quillen
et al, 2021b), where they assume that the worms inhibit the motion
of their neighbors when they overlap—effectively a mechanical cou-
pling. This type of synchronization of oscillatory motion has also
been recovered with robots (Zhou et al, 2021, Box 2). These exam-
ples show how even the most basic forms of “mechanics”—pushing
through contact—can lead to patterns.
Finally, the understanding of metachronal waves through theo-
retical modeling has also helped in the design and construction of
artificial carpets of cilia, whose metachronal waves can be
harnessed to generate desired fluid flows and transport (see, e.g., Ul
Islam et al, 2022, for a review).
Conclusions
The importance of mechanics and shape in biology has been appre-
ciated for a long time (Thompson, 1917). However, more recently,
experimental advances have allowed quantitative measurements of
forces, flows, and shapes of cells and tissues. It is now clear that
mechanical and geometrical properties of cells and tissues play an
essential role in biological organization and function across diverse
contexts and scales (e.g., Gross et al, 2017; Naganathan & Oates,
2017; Hannezo & Heisenberg, 2019; Maroudas-Sacks & Keren, 2021;
Bailles et al, 2022; Valet et al, 2022; Dullweber & Erzberger, 2023).
Feedback between mechanical changes, shape dynamics, and bio-
chemical or genetic regulatory processes leads to the formation of
mechanochemical patterns.
In this review, we highlighted theoretical developments, mostly
from recent years, on mechanical and mechanochemical pattern for-
mation. We discussed in particular how systems on spatial scales
spanning 1-10000μm and levels of biological organization from sub-
cellular to organismal are governed by the same physics. The fact
that these systems can be described by the same equations illus-
trates the generality of some of the outlined mechanochemical
pattern-forming mechanisms. Theoretical approaches have been
crucial to uncover these common mechanisms. Conversely, mecha-
nochemical pattern formation has spurred the development of new
theories, leading to new insights into the physics of complex sys-
tems (Prost et al, 2015; Bowick et al, 2022; National Academies of
Sciences, Engineering, and Medicine, 2022; Hallatschek et al, 2023).
The main theoretical tool we focused on is linear stability analy-
sis. Even though the premise of this approach is that the system is
EMBO reports 24: e57739 | 2023 17 of 24
EMBO reports
close to a steady state, it proves to be remarkably useful in under-
standing pattern formation in general settings. Yet, a more complete
understanding of patterns, including their long-time behavior, can
require additional theoretical tools or computer simulations (Box 2).
In many living systems, processes are coupled across different spatio-
temporal scales and levels of biological organization. For example, in
some cases, pattern formation in a tissue can be described by contin-
uum equations, treating the cells as microscopic units whose dynam-
ics can be described by fields, but sometimes the cell’s individual
features matter too, in which case a model with cells as discrete units
may be more appropriate. In particular, when microscopic units
adapt and respond to changes at larger scales, behaviors can arise
that are not seen in passive physical systems, motivating theoretical
approaches that not only explain how large-scale phenomena arise
from microscopic dynamics but which can also capture the effects of
scale-crossing bidirectional interactions.
In this review, we have discussed only deterministic models and
did not touch upon the role of noise and stochasticity. However,
noise is always present in biological systems, and how noise is
involved in giving rise to structures or processes with biological
functions is an intriguing question, also in the context of pattern for-
mation. For example, stochastic effects can lead to
large-amplitude patterns in systems that, when considered deter-
ministically, exhibit a stable homogeneous steady state (e.g., Bian-
calani et al, 2017; Karig et al, 2018).
Forces, flows, and geometry can induce feedback on time and
length scales very different from those accessible to molecular
mechanisms. Coupling biological regulatory mechanisms to
mechanics or geometry can therefore enable dynamics or patterns
difficult to attain otherwise. Generally, rich dynamical phenomena
are the result of feedback terms in the governing equations. In bio-
chemical systems, such feedbacks typically involve multiple interac-
tions and non-linearities. Importantly, however, mechanochemical
coupling can lead to complex phenomena with no cost or even with
an improvement to the parsimony of our theoretical understanding.
Cells do not escape the laws of physics, or in other words, mechan-
ics and shape are always there, and including them in theoretical
descriptions of biological systems often leads to simpler explana-
tions for observed phenomena. In fact, neglecting fundamental
physical properties can require complicated implicit assumptions
that are unjustified, unrealistic, or even impossible. Non-linearities
are required for pattern formation, and in models that focus exclu-
sively on biochemical effects, these must be postulated to arise
purely from molecular interactions. In the Schnakenberg equations,
Box 2. In need of answers.
1. How did biological pattern-forming systems evolve? How was
their evolution facilitated or constrained by physical factors such
as mechanics and geometry?
2. What biological functions are driven by mechanochemical
patterning?
3. How to study—analytically and numerically—pattern formation
on domains that undergo large deformations and/or topological
changes?
4. Can we harness principles of mechanochemical pattern forma-
tion to build or control artificial systems?
18 of 24 EMBO reports 24: e57739 | 2023
Jan Rombouts et al
for example (equations 19, Box 1), the non-linearity arises from a
trimolecular reaction term with a single rate constant. For mass
action kinetics, this is unrealistic since it requires the simultaneous
collision of three molecules with a non-negligible probability. Many
biochemical pattern-forming models make assumptions of—often
unknown—reactions that are summarized by a few non-linear
terms. Taking the—typically known—effects of mechanics and
geometry into account can make invoking additional biochemical
complexity unnecessary.
The inevitability of geometry and mechanical interactions raises
the question of how patterns that rely on mechanics have evolved,
and whether mechanical pattern formation is more robust com-
pared to genetic or biochemical patterns (Box 2). It will be inter-
esting to investigate—for specific cases and across different
contexts—whether patterns or their functions become less vulnera-
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
ble to variations in parameter values when they are generated by
mechanochemical feedback mechanisms. We expect that a deeper
understanding of these questions, and progress toward answers,
will require a strong interaction between experimental advances
and theoretical approaches.
Acknowledgements
We are grateful to Nir Gov, Oane Gros, Edouard Hannezo, Prachiti Moghe,
Mindy Perkins, Michael Zhao, and all members of the Erzberger group for
feedback and discussions on the manuscript. JE and AE are funded by the
European Molecular Biology Laboratory. JR is supported by an EMBL
Interdisciplinary Postdoctoral Fellowship (EIPOD4) program under Marie
Sklodowska-Curie Actions Cofund (grant agreement no. 847543). Open Access
funding enabled and organized by Projekt DEAL.
Author contributions
Jan Rombouts: Conceptualization; formal analysis; funding acquisition;
visualization; writing – original draft; writing – review and editing. Jenna
Elliott: Conceptualization; formal analysis; visualization; writing – original
draft; writing – review and editing. Anna Erzberger: Conceptualization;
supervision; funding acquisition; visualization; writing – original draft; writing
– review and editing.
Disclosure and competing interests statement
The authors declare that they have no conflict of interest.
References
Abrams DM, Strogatz SH (2004) Chimera states for coupled oscillators. Phys
Rev Lett 93: 174102
Agudo-Canalejo J, Golestanian R (2017) Pattern formation by curvature-
inducing proteins on spherical membranes. New J Phys 19: 125013
Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002) The lipid
bilayer. In Molecular Biology of the Cell, 4th edn. New York, NY: Garland
Science
Alert R, Trepat X (2020) Physical models of collective cell migration. Annu Rev
Condens Matter Phys 11: 77 – 101
Alimohamadi H, Rangamani P (2018) Modeling membrane curvature
generation due to membrane–protein interactions. Biomolecules 8: 120
Almet AA, Maini PK, Moulton DE, Byrne HM (2020) Modeling perspectives on
the intestinal crypt, a canonical system for growth, mechanics, and
remodeling. Curr Opin Biomed Eng 15: 32 – 39
 2023 The Authors
Jan Rombouts et al
Alt S, Ganguly P, Salbreux G (2017) Vertex models: from cell mechanics to
tissue morphogenesis. Philos Trans R Soc Lond B Biol Sci 372: 20150520
Ambrosi D, Ben Amar M, Cyron CJ, DeSimone A, Goriely A, Humphrey JD, Kuhl
E (2019) Growth and remodelling of living tissues: perspectives, challenges
and opportunities. J R Soc Interface 16: 20190233
Aoki K, Kondo Y, Naoki H, Hiratsuka T, Itoh RE, Matsuda M (2017)
Propagating wave of ERK activation orients collective cell migration. Dev
Cell 43: 305 – 317
Argudo D, Bethel NP, Marcoline FV, Grabe M (2016) Continuum descriptions
of membranes and their interaction with proteins: towards chemically
accurate models. Biochim Biophys Acta 1858: 1619 – 1634
Ayed SH, Cloutier AD, McLeod LJ, Foo ACY, Damry AM, Goto NK (2017)
Dissecting the role of conformational change and membrane binding by
the bacterial cell division regulator MinE in the stimulation of MinD
ATPase activity. J Biol Chem 292: 20732 – 20743
Bailles A, Gehrels EW, Lecuit T (2022) Mechanochemical principles of spatial
and temporal patterns in cells and tissues. Annu Rev Cell Dev Biol 38:
321 – 347
Banerjee S, Utuje KJC, Marchetti MC (2015) Propagating stress waves during
epithelial expansion. Phys Rev Lett 114: 228101
Barakat JM, Squires TM (2022) Curvature-mediated forces on elastic
inclusions in fluid interfaces. Langmuir 38: 1099 – 1105
Bassereau P, Sorre B, Levy A (2014) Bending lipid membranes: experiments
after W. Helfrich’s model. Adv Colloid Interface Sci 208: 47 – 57
Begemann I, Saha T, Lamparter L, Rathmann I, Grill D, Golbach L, Rasch C,
Keller U, Trappmann B, Matis M et al (2019) Mechanochemical self-
organization determines search pattern in migratory cells. Nat Phys 15:
848 – 857
Belousov R, Savino S, Moghe P, Hiiragi T, Rondoni L, Erzberger A (2023) When
time matters: poissonian cellular Potts models reveal nonequilibrium
kinetics of cell sorting. arXiv https://arxiv.org/abs/2306.04443 [PREPRINT]
Berg HC (1993) Random walks in biology. Princeton, NJ: Princeton University
Press
Bergert M, Erzberger A, Desai RA, Aspalter IM, Oates AC, Charras G, Salbreux
G, Paluch EK (2015) Force transmission during adhesion-independent
migration. Nat Cell Biol 17: 524 – 529
Beroz F, Yan J, Meir Y, Sabass B, Stone HA, Bassler BL, Wingreen NS (2018)
Verticalization of bacterial biofilms. Nat Phys 14: 954 – 960
Beta C, Kruse K (2017) Intracellular oscillations and waves. Annu Rev Condens
Matter Phys 8: 239 – 264
Biancalani T, Jafarpour F, Goldenfeld N (2017) Giant amplification of noise in
fluctuation-induced pattern formation. Phys Rev Lett 118: 018101
Bischof J, Brand CA, Somogyi K, Majer I, Thome S, Mori M, Schwarz US,
Len
art P (2017) A cdk1 gradient guides surface contraction waves in
oocytes. Nat Commun 8: 849
Blanch-Mercader C, Casademunt J (2017) Hydrodynamic instabilities, waves
and turbulence in spreading epithelia. Soft Matter 13: 6913 – 6928
Bloom M, Evans E, Mouritsen OG (1991) Physical properties of the fluid lipid-
bilayer component of cell membranes: a perspective. Q Rev Biophys 24:
293 – 397
de Boer PA, Crossley RE, Rothfield LI (1989) A division inhibitor and a
topological specificity factor coded for by the minicell locus determine
proper placement of the division septum in E. coli. Cell 56: 641 – 649
Bois JS, Jülicher F, Grill SW (2011) Pattern formation in active fluids. Phys Rev
Lett 106: 028103
Bonny M, Fischer-Friedrich E, Loose M, Schwille P, Kruse K (2013) Membrane
binding of MinE allows for a comprehensive description of min-protein
pattern formation. PLoS Comput Biol 9: e1003347
 2023 The Authors
EMBO reports
Boocock D, Hino N, Ruzickova N, Hirashima T, Hannezo E (2021) Theory of
mechanochemical patterning and optimal migration in cell monolayers.
Nat Phys 17: 267 – 274
Bowick MJ, Fakhri N, Marchetti MC, Ramaswamy S (2022) Symmetry,
thermodynamics, and topology in active matter. Phys Rev X
12: 010501
Brangwynne CP, MacKintosh FC, Kumar S, Geisse NA, Talbot J, Mahadevan L,
Parker KK, Ingber DE, Weitz DA (2006) Microtubules can bear enhanced
compressive loads in living cells because of lateral reinforcement. J Cell
Biol 173: 733 – 741
Brau F, Damman P, Diamant H, Witten TA (2013) Wrinkle to fold transition:
influence of the substrate response. Soft Matter 9: 8177 – 8186
Brauns F, Halatek J, Frey E (2020) Phase-space geometry of mass-conserving
reaction-diffusion dynamics. Phys Rev X 10: 041036
Brauns F, Pawlik G, Halatek J, Kerssemakers J, Frey E, Dekker C (2021)
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
Bulk-surface coupling identifies the mechanistic connection between
Min-protein patterns in vivo and in vitro. Nat Commun 12: 3312
Brumley DR, Wan KY, Polin M, Goldstein RE (2014) Flagellar synchronization
through direct hydrodynamic interactions. Elife 3: e02750
Brumley DR, Bruot N, Kotar J, Goldstein RE, Cicuta P, Polin M (2016) Long-
range interactions, wobbles, and phase defects in chains of model cilia.
Phys Rev Fluids 1: 081201
Byron ML, Murphy DW, Katija K, Hoover AP, Daniels J, Garayev K, Takagi D, Kanso
E, Gemmell BJ, Ruszczyk M et al (2021) Metachronal motion across scales:
current challenges and future directions. Integr Comp Biol 61: 1674 – 1688
Cail RC, Drubin DG (2023) Membrane curvature as a signal to ensure
robustness of diverse cellular processes. Trends Cell Biol 33: 427 – 441
Callan-Jones AC, Ruprecht V, Wieser S, Heisenberg CP, Voituriez R (2016)
Cortical flow-driven shapes of nonadherent cells. Phys Rev Lett 116: 1 – 5
Canham PB (1970) The minimum energy of bending as a possible
explanation of the biconcave shape of the human red blood cell. J Theor
Biol 26: 61 – 81
Carlquist WC, Cytrynbaum EN (2021) The mechanism of MinD stability
modulation by MinE in Min protein dynamics. bioRxiv https://doi.org/10.
1101/2021.07.30.454523 [PREPRINT]
Carman PJ, Dominguez R (2018) Bar domain proteins—a linkage between
cellular membranes, signaling pathways, and the actin cytoskeleton.
Biophys Rev 10: 1587 – 1604
Chakrabarti B, Fiirthauer S, Shelley MJ (2022) A multiscale biophysical model
gives quantized metachronal waves in a lattice of beating cilia. Proc Natl
Acad Sci U S A 119: e2113539119
Chan CJ, Heisenberg C-P, Hiiragi T (2017) Coordination of morphogenesis and
cell-fate specification in development. Curr Biol 27: R1024 – R1035
Collier JR, Monk NAM, Maini PK, Lewis JH (1996) Pattern formation by lateral
inhibition with feedback: a mathematical model of delta-notch
intercellular signalling. J Theor Biol 183: 429 – 446
Collinet C, Lecuit T (2021) Programmed and self-organized flow of
information during morphogenesis. Nat Rev Mol Cell Biol 22: 245 – 265
Cooke IR, Deserno M (2006) Coupling between lipid shape and membrane
curvature. Biophys J 91: 487 – 495
Crook S, Ermentrout G, Vanier M, Bower J (1997) The role of axonal delay in
the synchronization of networks of coupled cortical oscillators. J Comput
Neurosci 4: 161 – 172
Cross M, Greenside H (2009) Pattern formation and dynamics in
nonequilibrium systems. Cambridge: Cambridge University Press
Curantz C, Bailleul R, Castro-Scherianz M, Hidalgo M, Durande M, Graner F,
Manceau M (2022) Cell shape anisotropy contributes to selforganized
feather pattern fidelity in birds. PLoS Biol 20: e3001807
EMBO reports 24: e57739 | 2023 19 of 24
EMBO reports
Cytrynbaum EN, Marshall BDL (2007) A multistranded polymer model
explains MinDE dynamics in E. coli cell division. Biophys J 93: 1134 – 1150
Dasanayake NL, Michalski PJ, Carlsson AE (2011) General mechanism of
actomyosin contractility. Phys Rev Lett 107: 118101
De Gennes PG, Taupin C (1982) Microemulsions and the flexibility of oil/water
interfaces. J Phys Chem 86: 2294 – 2304
Denk J, Kretschmer S, Halatek J, Hartl C, Schwille P, Frey E (2018) MinE
conformational switching confers robustness on self-organized Min
protein patterns. Proc Natl Acad Sci U S A 115: 4553 – 4558
Deserno M (2015) Fluid lipid membranes: from differential geometry to
curvature stresses. Chem Phys Lipids 185: 11 – 45
Deserno M, Kremer K, Paulsen H, Peter C, Schmid F (2014) Computational
studies of biomembrane systems: theoretical considerations,
simulation models, and applications. In From Single Molecules to
Nanoscopically Structured Materials, Advances in Polymer Science, Basche
T, Müllen K, Schmidt M (eds), pp 237 – 283. Cham: Springer International
Publishing
Dierkes K, Sumi A, Solon J, Salbreux G (2014) Spontaneous oscillations of
elastic contractile materials with turnover. Phys Rev Lett 113: 148102
Dimova R (2014) Recent developments in the field of bending rigidity
measurements on membranes. Adv Colloid Interface Sci 208:
225 – 234
Doktorova M, Harries D, Khelashvili G (2017) Determination of bending
rigidity and tilt modulus of lipid membranes from real-space
fluctuation analysis of molecular dynamics simulations. Phys Chem
Chem Phys 19: 16806 – 16818
Doskocz J, Drabik D, Chodaczek G, Przybylo M, Langner M (2018) Statistical
analysis of bending rigidity coefficient determined using fluorescence-
based flicker-noise spectroscopy. J Membr Biol 251: 601 – 608
Drew DA, Osborn MJ, Rothfield LI (2005) A polymerization-depolymerization
model that accurately generates the self-sustained oscillatory system
involved in bacterial division site placement. Proc Natl Acad Sci U S A 102:
6114 – 6118
Dullweber T, Erzberger A (2023) Mechanochemical feedback loops in contact-
dependent fate patterning. Curr Opin Syst Biol 32–33: 100445
Dymond MK (2021) Lipid monolayer spontaneous curvatures: a collection of
published values. Chem Phys Lipids 239: 105117
Erzberger A, Jacobo A, Dasgupta A, Hudspeth AJ (2020) Mechanochemical
symmetry breaking during morphogenesis of lateral-line sensory organs.
Nat Phys 16: 949 – 957
Fei C, Mao S, Yan J, Alert R, Stone HA, Bassler BL, Wingreen NS, Kosmrlj A
(2020) Nonuniform growth and surface friction determine bacterial
biofilm morphology on soft substrates. Proc Natl Acad Sci U S A 117:
7622 – 7632
Fick A (1855) V. On liquid diffusion. The London, Edinburgh, and Dublin
Philosophical Magazine and J Sci 10: 30 – 39
Fofonjka A, Milinkovitch MC (2021) Reaction-diffusion in a growing 3D
domain of skin scales generates a discrete cellular automaton. Nat
Commun 12: 2433
Frey F, Idema T (2021) More than just a barrier: using physical models to
couple membrane shape to cell function. Soft Matter 17: 3533 – 3549
Gierer A, Meinhardt H (1972) A theory of biological pattern formation.
Kybernetik 12: 30 – 39
Gilpin W, Bull MS, Prakash M (2020) The multiscale physics of cilia and
flagella. Nat Rev Phys 2: 74 – 88
Glock P, Ramm B, Heermann T, Kretschmer S, Schweizer J, Miicksch J, Alagoz
G, Schwille P (2019) Stationary patterns in a two-protein reaction-
diffusion system. ACS Synth Biol 8: 148 – 157
20 of 24 EMBO reports 24: e57739 | 2023
Jan Rombouts et al
Gordon VD, Davis-Fields M, Kovach K, Rodesney CA (2017) Biofilms and
mechanics: a review of experimental techniques and findings. J Phys D
Appl Phys 50: 223002
Goriely A (2017) The mathematics and mechanics of biological growth, Vol. 45,
Interdisciplinary applied mathematics. New York, NY: Springer
Gov NS (2018) Guided by curvature: shaping cells by coupling curved
membrane proteins and cytoskeletal forces. Philos Trans R Soc Lond B Biol
Sci 373: 20170115
Graner F, Glazier JA (1992) Simulation of biological cell sorting using a two-
dimensional extended Potts model. Phys Rev Lett 69: 2013 – 2016
Green JBA, Sharpe J (2015) Positional information and reaction-diffusion:
two big ideas in developmental biology combine. Development 142:
1203 – 1211
Gross P, Kumar KV, Grill SW (2017) How active mechanics and regulatory
biochemistry combine to form patterns in development. Annu Rev Biophys
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
46: 337 – 356
Guckenberger A, Gekle S (2017) Theory and algorithms to compute Helfrich
bending forces: a review. J Phys Condens Matter 29: 203001
Guerrier S, Coutinho-Budd J, Sassa T, Gresset A, Jordan NV, Chen K, Jin W-L,
Frost A, Polleux F (2009) The F-BAR domain of srGAP2 induces membrane
protrusions required for neuronal migration and morphogenesis. Cell 138:
990 – 1004
Guo K, Huang C, Miao Y, Cosgrove DJ, Hsia KJ (2022) Leaf morphogenesis: the
multifaceted roles of mechanics. Mol Plant 15: 1098 – 1119
Gutjahr P, Lipowsky R, Kierfeld J (2006) Persistence length of semiflexible
polymers and bending rigidity renormalization. Europhys Lett 76: 994 – 1000
Haas PA, Goldstein RE (2021) Turing’s diffusive threshold in random reaction-
diffusion systems. Phys Rev Lett 126: 238101
Halatek J, Frey E (2012) Highly canalized MinD transfer and MinE
sequestration explain the origin of robust MinCDE-protein dynamics. Cell
Rep 1: 741 – 752
Halatek J, Frey E (2018) Rethinking pattern formation in reaction-diffusion
systems. Nat Phys 14: 507 – 514
Halatek J, Brauns F, Frey E (2018) Self-organization principles of
intracellular pattern formation. Philos Trans R Soc Lond B Biol Sci 373:
20170107
Hallatschek O, Datta SS, Drescher K, Dunkel J, Elgeti J, Waclaw B, Wingreen
NS (2023) Proliferating active matter. Nat Rev Phys 5: 1 – 13
Hamaguchi MS, Hiramoto Y (1978) Protoplasmic movement during polar-
body formation in starfish oocytes. Exp Cell Res 112: 55 – 62
Hannezo E, Heisenberg C-P (2019) Mechanochemical feedback loops in
development and disease. Cell 178: 12 – 25
Hannezo E, Prost J, Joanny J-F (2011) Instabilities of monolayered epithelial
shape and structure of villi and crypts. Phys Rev Lett 107: 078104
Hannezo E, Prost J, Joanny J-F (2012) Mechanical instabilities of biological
tubes. Phys Rev Lett 109: 018101
Hannezo E, Dong B, Recho P, Joanny J-F, Hayashi S (2015) Cortical instability
drives periodic supracellular actin pattern formation in epithelial tubes.
Proc Natl Acad Sci U S A 112: 8620 – 8625
Happel J, Brenner H (1983) Low Reynolds number hydrodynamics: with special
applications to particulate media, Vol. 1. Mechanics of fluids and transport
processes. Dordrecht: Springer Netherlands
Harris AK, Warner P, Stopak D (1984) Generation of spatially periodic patterns
by a mechanical instability: a mechanical alternative to the Turing model.
Development 80: 1 – 20
Haselwandter CA, Wingreen NS (2014) The role of membrane-mediated
interactions in the assembly and architecture of chemoreceptor lattices.
PLoS Comput Biol 10: e1003932
 2023 The Authors
Jan Rombouts et al
Haussman RC, Deserno M (2014) Effective field theory of thermal Casimir
interactions between anisotropic particles. Phys Rev E Stat Nonlin Soft
Matter Phys 89: 062102
Hawkins RJ, Poincloux R, Benichou O, Piel M, Chavrier P, Voituriez R (2011)
Spontaneous contractility-mediated cortical flow generates cell migration
in three-dimensional environments. Biophys J 101: 1041 – 1045
Heinrich MC, Capraro BR, Tian A, Isas JM, Langen R, Baumgart T (2010)
Quantifying membrane curvature generation of drosophila amphiphysin
N-BAR domains. J Phys Chem Lett 1: 3401 – 3406
Helfrich W (1973) Elastic properties of lipid bilayers: theory and possible
experiments. Z Naturforsch C 28: 693 – 703
Hino N, Rossetti L, Marin-Llaurado A, Aoki K, Trepat X, Matsuda M, Hirashima
T (2020) ERK-mediated mechanochemical waves direct collective cell
polarization. Dev Cell 53: 646 – 660
Hirashima T, Hino N, Aoki K, Matsuda M (2023) Stretching the limits of
extracellular signal-related kinase (ERK) signaling — cell mechanosensing
to ERK activation. Curr Opin Cell Biol 84: 102217
Hiratsuka T, Fujita Y, Naoki H, Aoki K, Kamioka Y, Matsuda M (2015)
Intercellular propagation of extracellular signal-regulated kinase activation
revealed by in vivo imaging of mouse skin. Elife 4: e05178
Hossein A, Deserno M (2020) Spontaneous curvature, differential stress, and
bending modulus of asymmetric lipid membranes. Biophys J 118: 624 – 642
Howard J, Grill SW, Bois JS (2011) Turing’s next steps: the mechanochemical
basis of morphogenesis. Nat Rev Mol Cell Biol 12: 392 – 398
Hu Z, Lutkenhaus J (1999) Topological regulation of cell division in Escherichia
coli involves rapid pole to pole oscillation of the division inhibitor MinC
under the control of MinD and MinE. Mol Microbiol 34: 82 – 90
Huang KC, Meir Y, Wingreen NS (2003) Dynamic structures in Escherichia coli:
spontaneous formation of MinE rings and MinD polar zones. Proc Natl
Acad Sci U S A 100: 12724 – 12728
Ivanov V, Mizuuchi K (2010) Multiple modes of interconverting dynamic
pattern formation by bacterial cell division proteins. Proc Natl Acad Sci U S
A 107: 8071 – 8078
Johannes L, Pezeshkian W, Ipsen JH, Shillcock JC (2018) Clustering on
membranes: fluctuations and more. Trends Cell Biol 28: 405 – 415
Jülicher F, Grill SW, Salbreux G (2018) Hydrodynamic theory of active matter.
Rep Prog Phys 81: 076601
Karig D, Martini KM, Lu T, DeLateur NA, Goldenfeld N, Weiss R (2018)
Stochastic Turing patterns in a synthetic bacterial population. Proc Natl
Acad Sci U S A 115: 6572 – 6577
Kelkar M, Bohec P, Charras G (2020) Mechanics of the cellular actin cortex:
from signalling to shape change. Curr Opin Cell Biol 66: 69 – 78
Kindberg A, Hu JK, Bush JO (2020) Forced to communicate: integration of
mechanical and biochemical signaling in morphogenesis. Curr Opin Cell
Biol 66: 59 – 68
Klughammer N, Bischof J, Schnellbacher ND, Callegari A, Lenart P, Schwarz
US (2018) Cytoplasmic flows in starfish oocytes are fully determined by
cortical contractions. PLoS Comput Biol 14: e1006588
Koduru S, Kumar L, Massaad MJ, Ramesh N, Le Bras S, Ozcan E, Oyoshi MK,
Kaku M, Fujiwara Y, Kremer L et al (2010) Cdc42 interacting protein 4
(CIP4) is essential for integrin-dependent T-cell trafficking. Proc Natl Acad
Sci U S A 107: 16252 – 16256
Kruse K, Joanny JF, Jülicher F, Prost J, Sekimoto K (2005) Generic theory of
active polar gels: a paradigm for cytoskeletal dynamics. Eur Phys J E Soft
Matter 16: 5 – 16
Kumar KV, Bois JS, Jülicher F, Grill SW (2014) Pulsatory patterns in active
fluids. Phys Rev Lett 112: 208101
 2023 The Authors
EMBO reports
Kuramoto Y, Battogtokh D (2002) Coexistence of coherence and incoherence
in nonlocally coupled phase oscillators. Nonlinear Phenom Complex Syst 5:
380
Kurtisovski E, Taulier N, Ober R, Waks M, Urbach W (2007) Molecular origin
of model membrane bending rigidity. Phys Rev Lett 98: 258103
Kwiecinski J, Chapman SJ, Goriely A (2017) Self-assembly of a filament by
curvature-inducing proteins. Phys D Nonlinear Phenom 344: 68 – 80
Lauga E, Powers TR (2009) The hydrodynamics of swimming microorganisms.
Rep Prog Phys 72: 096601
Leibler S (1986) Curvature instability in membranes. J Phys 47: 507 – 516
Lin S, Hirayama D, Maryu G, Matsuda K, Hino N, Deguchi E, Aoki K, Iwamoto
R, Terai K, Matsuda M (2022) Redundant roles of EGFR ligands in the ERK
activation waves during collective cell migration. Life Sci Alliance 5:
e202101206
Lipowsky R, Döbereiner H-G, Hiergeist C, Indrani V (1998) Membrane
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
curvature induced by polymers and colloids. Physica A 249: 536 – 543
Liu J, Sun Y, Drubin DG, Oster GF (2009) The mechanochemistry of
endocytosis. PLoS Biol 7: e1000204
Liu Y-J, Le Berre M, Lautenschlaeger F, Maiuri P, Callan-Jones A, Heuze M,
Takaki T, Voituriez R, Piel M (2015) Confinement and low adhesion
induce fast amoeboid migration of slow mesenchymal cells. Cell 160:
659 – 672
Llinares-Benadero C, Borrell V (2019) Deconstructing cortical folding: genetic,
cellular and mechanical determinants. Nat Rev Neurosci 20: 161 – 176
Loose M, Fischer-Friedrich E, Ries J, Kruse K, Schwille P (2008) Spatial
regulators for bacterial cell division self-organize into surface waves in
vitro. Science 320: 789 – 792
Loose M, Fischer-Friedrich E, Herold C, Kruse K, Schwille P (2011) Min protein
patterns emerge from rapid rebinding and membrane interaction of MinE.
Nat Struct Mol Biol 18: 577 – 583
Lutkenhaus J (2007) Assembly dynamics of the bacterial MinCDE system and
spatial regulation of the Z ring. Annu Rev Biochem 76: 539 – 562
Mahapatra A, Saintillan D, Rangamani P (2021) Curvature-driven feedback on
aggregation-diffusion of proteins in lipid bilayers. Soft Matter 17: 8373 – 8386
Manukyan L, Montandon SA, Fofonjka A, Smirnov S, Milinkovitch MC (2017) A
living mesoscopic cellular automaton made of skin scales. Nature 544:
173 – 179
Marchetti MC, Joanny J-F, Ramaswamy S, Liverpool TB, Prost J, Rao M, Simha RA
(2013) Hydrodynamics of soft active matter. Rev Mod Phys 85: 1143 – 1189
Marcon L, Diego X, Sharpe J, Möller P (2016) High-throughput mathematical
analysis identifies Turing networks for patterning with equally diffusing
signals. Elife 5: e14022
Maroudas-Sacks Y, Keren K (2021) Mechanical patterning in animal
morphogenesis. Annu Rev Cell Dev Biol 37: 469 – 493
Meindlhumer S, Brauns F, Finzgar JR, Kerssemakers J, Dekker C, Frey E (2023)
Directing Min protein patterns with advective bulk flow. Nat Commun 14:
450
Meinhardt H (2012) Turing’s theory of morphogenesis of 1952 and the
subsequent discovery of the crucial role of local self-enhancement and
long-range inhibition. Interface Focus 2: 407 – 416
Meinhardt H, Boer PAJ d (2001) Pattern formation in Escherichia coli: a model
for the pole-to-pole oscillations of Min proteins and the localization of
the division site. Proc Natl Acad Sci U S A 98: 14202 – 14207
Mietke A, Jemseena V, Kumar KV, Sbalzarini IF, Jülicher F (2019a) Minimal
model of cellular symmetry breaking. Phys Rev Lett 123: 188101
Mietke A, Jülicher F, Sbalzarini IF (2019b) Self-organized shape dynamics of
active surfaces. Proc Natl Acad Sci U S A 116: 29 – 34
EMBO reports 24: e57739 | 2023 21 of 24
EMBO reports
Mim C, Unger VM (2012) Membrane curvature and its generation by BAR
proteins. Trends Biochem Sci 37: 526 – 533
Müller MM, Deserno M, Guven J (2005) Interface-mediated interactions
between particles: a geometrical approach. Phys Rev E 72: 061407
Murray JD (1982) Parameter space for Turing instability in reaction diffusion
mechanisms: a comparison of models. J Theor Biol 98: 143 – 163
Murray JD (2003) Mathematical biology: II: spatial models and biomedical
applications, Vol. 18. Interdisciplinary applied mathematics. New York, NY:
Springer
Naganathan SR, Oates AC (2017) Mechanochemical coupling and
developmental pattern formation. Curr Opin Syst Biol 5: 104 – 111
National Academies of Sciences, Engineering, and Medicine (2022) Physics of
life. Washington, DC: The National Academies Press
Nedelec F, Foethke D (2007) Collective Langevin dynamics of flexible
cytoskeletal fibers. New J Phys 9: 427
Needleman D, Dogic Z (2017) Active matter at the interface between
materials science and cell biology. Nat Rev Mater 2: 1 – 14
Nelson CM (2016) On buckling morphogenesis. J Biomech Eng 138: 021005
Niedermayer T, Eckhardt B, Lenz P (2008) Synchronization, phase locking, and
metachronal wave formation in ciliary chains. Chaos 18: 037128
Nijjer J, Li C, Zhang Q, Lu H, Zhang S, Yan J (2021) Mechanical forces drive a
reorientation cascade leading to biofilm self-patterning. Nat Commun 12:
6632
Nishide R, Ishihara S (2022) Pattern propagation driven by surface curvature.
Phys Rev Lett 128: 224101
Oriola D, Marin-Riera M, Anlas K, Gritti N, Sanaki-Matsumiya M, Aalderink G,
Ebisuya M, Sharpe J, Trivedi V (2022) Arrested coalescence of multicellular
aggregates. Soft Matter 18: 3771 – 3780
Oster GF, Murray JD, Harris AK (1983) Mechanical aspects of mesenchymal
morphogenesis. Development 78: 83 – 125
Painter KJ (2019) Mathematical models for chemotaxis and their applications
in self-organisation phenomena. J Theor Biol 481: 162 – 182
Painter KJ, Hillen T (2011) Spatio-temporal chaos in a chemotaxis model.
Physica D 240: 363 – 375
Palmquist KH, Tiemann SF, Ezzeddine FL, Yang S, Pfeifer CR, Erzberger A,
Rodrigues AR, Shyer AE (2022) Reciprocal cell-ECM dynamics generate
supracellular fluidity underlying spontaneous follicle patterning. Cell 185:
1960 – 1973
Park K-T, Wu W, Battaile KP, Lovell S, Holyoak T, Lutkenhaus J (2011) The min
oscillator uses MinD-dependent conformational changes in MinE to
spatially regulate cytokinesis. Cell 146: 396 – 407
Peleg B, Disanza A, Scita G, Gov N (2011) Propagating cell-membrane
waves driven by curved activators of actin polymerization. PLoS One 6:
e18635
Peliti L, Leibler S (1985) Effects of thermal fluctuations on systems with small
surface tension. Phys Rev Lett 54: 1690 – 1693
Peshkov A, McGaffigan S, Quillen AC (2022) Synchronized oscillations in
swarms of nematode Turbatrix aceti. Soft Matter 18: 1174 – 1182
 Z, Heisenberg C-P (2017) Multiscale force sensing in
Petridou NI, Spiro
development. Nat Cell Biol 19: 581 – 588
Peyret G, Mueller R, d’Alessandro J, Begnaud S, Marcq P, Mege R-M, Yeomans
JM, Doostmohammadi A, Ladoux B (2019) Sustained oscillations of
epithelial cell sheets. Biophys J 117: 464 – 478
Pikovsky A, Kurths J, Rosenblum M, Kurths J (2003) Synchronization: a universal
concept in nonlinear sciences. Cambridge: Cambridge University Press
Prost J, Jülicher F, Joanny J-F (2015) Active gel physics. Nat Phys 11: 111 – 117
Purcell EM (1977) Life at low Reynolds number. Am J Phys 45: 3 – 11
22 of 24 EMBO reports 24: e57739 | 2023
Jan Rombouts et al
Quaas J, Wylie C (2002) Surface contraction waves (SCWs) in the Xenopus
egg are required for the localization of the germ plasm and are
dependent upon maternal stores of the kinesin-like protein Xklp1. Dev Biol
243: 272 – 280
Quillen AC (2023) Robust formation of metachronal waves in directional
chains of phase oscillators. Phys Rev E 107: 034401
Quillen AC, Peshkov A, Wright E, McGaffigan S (2021a) Metachronal waves in
concentrations of swimming Turbatrix aceti nematodes and an oscillator
chain model for their coordinated motions. arXiv https://arxiv.org/abs/
2101.06809 [PREPRINT]
Quillen AC, Peshkov A, Wright E, McGaffigan S (2021b) Metachronal waves in
concentrations of swimming Turbatrix aceti nematodes and an oscillator
chain model for their coordinated motions. Phys Rev E 104: 014412
Ramakrishnan N, Sunil Kumar PB, Radhakrishnan R (2014) Mesoscale
computational studies of membrane bilayer remodeling by curvature-
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
inducing proteins. Phys Rep 543: 1 – 60
Ramaswamy S (2010) The mechanics and statistics of active matter. Annu
Rev Condens Matter Phys 1: 323 – 345
Ramaswamy S, Toner J, Prost J (2000) Nonequilibrium fluctuations, traveling
waves, and instabilities in active membranes. Phys Rev Lett 84: 3494 –
3497
Ramm B, Heermann T, Schwille P (2019) The E. coli MinCDE system in the
regulation of protein patterns and gradients. Cell Mol Life Sci 76: 4245 – 4273
Raskin DM, de Boer PAJ (1999) Rapid pole-to-pole oscillation of a protein
required for directing division to the middle of Escherichia coli. Proc Natl
Acad Sci U S A 96: 4971 – 4976
Ravid Y, Penic S, Mimori-Kiyosue Y, Suetsugu S, Iglic A, Gov NS (2023)
Theoretical model of membrane protrusions driven by curved active
proteins. Front Mol Biosci 10: 1153420
Renner LD, Weibel DB (2012) MinD and MinE interact with anionic
phospholipids and regulate division plane formation in Escherichia coli.
J Biol Chem 287: 38835 – 38844
Reymann A-C, Staniscia F, Erzberger A, Salbreux G, Grill SW (2016) Cortical
flow aligns actin filaments to form a furrow. Elife 5: e17807
Reynwar BJ, Illya G, Harmandaris VA, Müller MM, Kremer K, Deserno M (2007)
Aggregation and vesiculation of membrane proteins by curvature-
mediated interactions. Nature 447: 461 – 464
Ruprecht V, Wieser S, Callan-Jones A, Smutny M, Morita H, Sako K, Barone V,
Ritsch-Marte M, Sixt M, Voituriez R et al (2015) Cortical contractility
triggers a stochastic switch to fast amoeboid cell motility. Cell 160: 673 –
685
Saadaoui M, Rocancourt D, Roussel J, Corson F, Gros J (2020) A tensile ring
drives tissue flows to shape the gastrulating amniote embryo. Science 367:
453 – 458
Sadhu RK, Penič S, Iglič A, Gov NS (2021) Modelling cellular spreading and
emergence of motility in the presence of curved membrane proteins
and active cytoskeleton forces. Eur Phys J Plus 136: 495
Sadhu RK, Hernandez-Padilla C, Eisenbach YE, Penič S, Zhang L, Vishwasrao
HD, Behkam B, Konstantopoulos K, Shroff H, Iglič A et al (2023)
Experimental and theoretical model for the origin of coiling of cellular
protrusions around fibers. Nat Commun 14: 5612
Salbreux G, Charras G, Paluch E (2012) Actin cortex mechanics and cellular
morphogenesis. Trends Cell Biol 22: 536 – 545
Sampathkumar A (2020) Mechanical feedback-loop regulation of
morphogenesis in plants. Development 147: dev177964
Savin T, Kurpios NA, Shyer AE, Florescu P, Liang H, Mahadevan L, Tabin CJ
(2011) On the growth and form of the gut. Nature 476: 57 – 62
 2023 The Authors
Jan Rombouts et al
Sawai T (1982) Wavelike propagation of stretching and shrinkage in the
surface of the newt’s egg before the first cleavage. J Exp Zool 222:
59 – 68
Schamberger B, Ziege R, Anselme K, Ben Amar M, Bykowski M, Castro APG,
Cipitria A, Coles RA, Dimova R, Eder M et al (2023) Curvature in biological
systems: its quantification, emergence, and implications across the scales.
Adv Mater 35: 2206110
Schnakenberg J (1979) Simple chemical reaction systems with limit cycle
behaviour. J Theor Biol 81: 389 – 400
Schwarz US, Safran SA (2013) Physics of adherent cells. Rev Mod Phys 85:
1327 – 1381
Schwarz US, Balaban NQ, Riveline D, Bershadsky A, Geiger B, Safran SA (2002)
Calculation of forces at focal adhesions from elastic substrate data: the
effect of localized force and the need for regularization. Biophys J 83:
1380 – 1394
Schweizer J, Loose M, Bonny M, Kruse K, Monch I, Schwille P (2012) Geometry
sensing by self-organized protein patterns. Proc Natl Acad Sci U S A 109:
15283 – 15288
Shlomovitz R, Gov NS (2007) Membrane waves driven by actin and myosin.
Phys Rev Lett 98: 168103
Shlomovitz R, Gov NS (2009) Membrane-mediated interactions drive the
condensation and coalescence of FtsZ rings. Phys Biol 6: 046017
Shyer AE, Tallinen T, Nerurkar NL, Wei Z, Gil ES, Kaplan DL, Tabin CJ,
Mahadevan L (2013) Villification: how the gut gets its villi. Science 342:
212 – 218
Shyer AE, Huycke TR, Lee C, Mahadevan L, Tabin CJ (2015) Bending gradients:
how the intestinal stem cell gets its home. Cell 161: 569 – 580
Shyer AE, Rodrigues AR, Schroeder GG, Kassianidou E, Kumar S, Harland RM
(2017) Emergent cellular self-organization and mechanosensation initiate
follicle pattern in the avian skin. Science 357: 811 – 815
Simunovic M, Voth GA, Callan-Jones A, Bassereau P (2015) When physics takes
over: BAR proteins and membrane curvature. Trends Cell Biol 25: 780 – 792
Sodt AJ, Pastor RW (2014) Molecular modeling of lipid membrane curvature
induction by a peptide: more than simply shape. Biophys J 106: 1958 – 1969
Solovev A, Friedrich BM (2022) Synchronization in cilia carpets: multiple
metachronal waves are stable, but one wave dominates. New J Phys 24:
013015
Sorre B, Callan-Jones A, Manzi J, Goud B, Prost J, Bassereau P, Roux A (2012)
Nature of curvature coupling of amphiphysin with membranes depends
on its bound density. Proc Natl Acad Sci U S A 109: 173 – 178
Streichan SJ, Lefebvre MF, Noll N, Wieschaus EF, Shraiman BI (2018) Global
morphogenetic flow is accurately predicted by the spatial distribution of
myosin motors. Elife 7: e27454
Takada S, Yoshinaga N, Doi N, Fujiwara K (2022) Mode selection mechanism
in traveling and standing waves revealed by Min wave reconstituted in
artificial cells. Sci Adv 8: eabm8460
Tanimoto H, Sano M (2014) A simple force-motion relation for migrating cells
revealed by multipole analysis of traction stress. Biophys J 106: 16 – 25
Thompson DW (1917) On growth and form. Cambridge: Cambridge University
Press
Tozluoğlu M, Mao Y (2020) On folding morphogenesis, a mechanical problem.
Philos Trans R Soc Lond B Biol Sci 375: 20190564
Tozluoğlu M, Duda M, Kirkland NJ, Barrientos R, Burden JJ, Munoz JJ, Mao Y
(2019) Planar differential growth rates initiate precise fold positions in
complex epithelia. Dev Cell 51: 299 – 312
Tozzi C, Walani N, Arroyo M (2019) Out-of-equilibrium mechanochemistry
and self-organization of fluid membranes interacting with curved
proteins. New J Phys 21: 093004
 2023 The Authors
EMBO reports
Trushko A, Di Meglio I, Merzouki A, Blanch-Mercader C, Abuhattum S, Guck J,
Alessandri K, Nassoy P, Kruse K, Chopard B et al (2020) Buckling of an
epithelium growing under spherical confinement. Dev Cell 54: 655 – 668
Tu ZC, Ou-Yang ZC (2014) Recent theoretical advances in elasticity of
membranes following Helfrich’s spontaneous curvature model. Adv Colloid
Interface Sci 208: 66 – 75
Turing AM (1952) The chemical basis of morphogenesis. Philos Trans R Soc
Lond B Biol Sci 237: 37 – 72
Uchida N, Golestanian R (2010) Synchronization and collective dynamics in a
carpet of microfluidic rotors. Phys Rev Lett 104: 178103
Ul Islam T, Wang Y, Aggarwal I, Cui Z, Eslami Amirabadi H, Garg H, Kooi R,
Venkataramanachar BB, Wang T, Zhang S et al (2022) Microscopic
artificial cilia – a review. Lab Chip 22: 1650 – 1679
Valet M, Siggia ED, Brivanlou AH (2022) Mechanical regulation of early
vertebrate embryogenesis. Nat Rev Mol Cell Biol 23: 169 – 184
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
Vecchiarelli AG, Li M, Mizuuchi M, Mizuuchi K (2014) Differential affinities of
MinD and MinE to anionic phospholipid influence Min patterning
dynamics in vitro. Mol Microbiol 93: 453 – 463
Vecchiarelli AG, Li M, Mizuuchi M, Hwang LC, Seol Y, Neuman KC, Mizuuchi K
(2016) Membrane-bound MinDE complex acts as a toggle switch that
drives Min oscillation coupled to cytoplasmic depletion of MinD. Proc Natl
Acad Sci U S A 113: E1479 – E1488
Vilfan A, Jülicher F (2006) Hydrodynamic flow patterns and synchronization
of beating cilia. Phys Rev Lett 96: 058102
Walsh JC, Angstmann CN, Bisson-Filho AW, Garner EC, Duggin IG, Curmi PMG
(2019) Division plane placement in pleomorphic archaea is dynamically
coupled to cell shape. Mol Microbiol 112: 785 – 799
Wan KY (2018) Coordination of eukaryotic cilia and flagella. Essays Biochem
62: 829 – 838
Wang N, Tytell JD, Ingber DE (2009) Mechanotransduction at a distance:
mechanically coupling the extracellular matrix with the nucleus. Nat Rev
Mol Cell Biol 10: 75 – 82
Weikl TR, Kozlov MM, Helfrich W (1998) Interaction of conical membrane
inclusions: effect of lateral tension. Phys Rev E 57: 6988 – 6995
Westwood TA, Keaveny EE (2021) Coordinated motion of active filaments on
spherical surfaces. Phys Rev Fluids 6: L121101
Wettmann L, Kruse K (2018) The Min-protein oscillations in Escherichia coli:
an example of self-organized cellular protein waves. Philos Trans R Soc
Lond B Biol Sci 373: 20170111
Wettmann L, Bonny M, Kruse K (2018) Effects of geometry and topography
on Min-protein dynamics. PLoS One 13: e0203050
Wigbers MC, Tan TH, Brauns F, Liu J, Swartz SZ, Frey E, Fakhri N (2021) A
hierarchy of protein patterns robustly decodes cell shape information. Nat
Phys 17: 578 – 584
Wiley DA, Strogatz SH, Girvan M (2006) The size of the sync basin. Chaos 16:
015103
Wollin C, Stark H (2011) Metachronal waves in a chain of rowers with
hydrodynamic interactions. Eur Phys J E 34: 42
Wollrab V, Thiagarajan R, Wald A, Kruse K, Riveline D (2016) Still and rotating
myosin clusters determine cytokinetic ring constriction. Nat Commun 7:
11860
Wu F, van Schie BG, Keymer JE, Dekker C (2015) Symmetry and scale orient
Min protein patterns in shaped bacterial sculptures. Nat Nanotechnol 10:
719 – 726
Wu Z, Su M, Tong C, Wu M, Liu J (2018) Membrane shape-mediated wave
propagation of cortical protein dynamics. Nat Commun 9: 136
Würger A (2000) Bending elasticity of surfactant films: the role of the
hydrophobic tails. Phys Rev Lett 85: 337 – 340
EMBO reports 24: e57739 | 2023 23 of 24
EMBO reports
Würthner L, Brauns F, Pawlik G, Halatek J, Kerssemakers J, Dekker C, Frey E
(2022) Bridging scales in a multiscale pattern-forming system. Proc Natl
Acad Sci U S A 119: e2206888119
Yan J, Fei C, Mao S, Moreau A, Wingreen NS, Kosmrlj A, Stone HA, Bassler BL
(2019) Mechanical instability and interfacial energy drive biofilm
morphogenesis. Elife 8: e43920
Yang S, Miao X, Arnold S, Li B, Ly AT, Wang H, Wang M, Guo X, Pathak MM,
Zhao W et al (2022) Membrane curvature governs the distribution of
Piezo1 in live cells. Nat Commun 13: 7467
Yeomans JM (2017) Nature’s engines: active matter. Europhys News 48:
21 – 25
Yolcu C, Haussman RC, Deserno M (2014) The Effective Field Theory
approach towards membrane-mediated interactions between particles.
Adv Colloid Interface Sci 208: 89 – 109
Yoneda M, Kobayakawa Y, Kubota HY, Sakai M (1982) Surface contraction
waves in amphibian eggs. J Cell Sci 54: 35 – 46
Yue T, Li S, Zhang X, Wang W (2010) The relationship between membrane
curvature generation and clustering of anchored proteins: a computer
simulation study. Soft Matter 6: 6109 – 6118
24 of 24 EMBO reports 24: e57739 | 2023
Jan Rombouts et al
Zaritsky A, Kaplan D, Hecht I, Natan S, Wolf L, Gov NS, Ben-Jacob E,
Tsarfaty I (2014) Propagating waves of directionality and
coordination orchestrate collective cell migration. PLoS Comput Biol 10:
e1003747
Zhou W, Hao Z, Gravish N (2021) Collective synchronization of undulatory
movement through contact. Phys Rev X 11: 031051
Zieske K, Schwille P (2013) Reconstitution of pole-to-pole oscillations of Min
proteins in microengineered polydimethylsiloxane compartments. Angew
Chem Int Ed 52: 459 – 462
Zieske K, Schwille P (2014) Reconstitution of self-organizing protein gradients
as spatial cues in cell-free systems. Elife 3: e03949
Zimmerberg J, Kozlov MM (2006) How proteins produce cellular membrane
curvature. Nat Rev Mol Cell Bio 7: 9 – 19
License: This is an open access article under the
Downloaded from https://www.embopress.org on February 11, 2024 from IP 89.12.171.35.
terms of the Creative Commons Attribution License,
which permits use, distribution and reproduction in
any medium, provided the original work is properly
cited.
 2023 The Authors