RECENTLY IN PRESS
Prospects & Overviews
The Mechanical Role of Microtubules in Tissue Remodeling
Maja Matis
During morphogenesis, tissues undergo extensive remodeling to get their
final shape. Such precise sculpting requires the application of forces
generated within cells by the cytoskeleton and transmission of these forces
through adhesion molecules within and between neighboring cells. Within
individual cells, microtubules together with actomyosin filaments and
intermediate filaments form the composite cytoskeleton that controls cell
mechanics during tissue rearrangements. While studies have established the
importance of actin-based mechanical forces that are coupled via intercellular
junctions, relatively little is known about the contribution of other cytoskeletal
components such as microtubules to cell mechanics during morphogenesis.
In this review the focus is on recent findings, highlighting the direct
mechanical role of microtubules beyond its well-established role in trafficking
and signaling during tissue formation.
1. Introduction
The contribution of microtubules to cell mechanics, cell-shape
changes and force coordination during morphogenesis is poorly
understood. This is mainly due to the lack of quantitative ap-
proaches to study local microtubule dynamics in cells with
high spatial and temporal precision, and the fact that many
studies focused on global observation rather than investigat-
ing the relationship between physico/mechanical and molecular
constituents.[1–4] To unravel the precise mechanisms harnessed
by the microtubule cytoskeleton during tissue development, im-
proved approaches to probe microtubule mechanical properties
in vivo with high spatiotemporal resolution are crucial. Recent
studies in Drosophila that will be discussed in this review pro-
vide for the first-time insights into the intricate relation between
microtubule organization, cell mechanics, and tissue level force
patterning.
Dr. M. Matis
Institute of Cell Biology
Medical Faculty
University of Münster
Münster 48149, Germany
E-mail: matism@uni-muenster.de
Dr. M. Matis
‘Cells in Motion’ Interfaculty Centre
University of Münster
Münster 48149, Germany
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/bies.201900244
© 2020 The Authors. BioEssays published by WILEY Periodicals, Inc. This
is an open access article under the terms of the Creative Commons
Attribution License, which permits use, distribution and reproduction in
any medium, provided the original work is properly cited.
DOI: 10.1002/bies.201900244
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Microtubules are indispensable struc-
tural elements in living systems, and their
mechanical properties are essential for a
vast array of cellular functions, including
cell shape, division, motility, intracellular
transport, and the generation of diverse cel-
lular shapes. The underpinning for their
mechanical resilience is provided by their
structure that makes them the most rigid
intracellular cytoskeletal filaments. Micro-
tubules are composed of alpha (𝛼) and beta
(𝛽) tubulin heterodimers that are assem-
bled into a cylindrical, hollow structure.
The uniform orientation of dimers within
the microtubule gives them intrinsic polar-
ity in which the 𝛼-tubulin faces the minus
end and 𝛽 units the plus end. Microtubules
are highly dynamic structures that display
growth and shrinkage, the kinetics of which is regulated
by microtubule-associated proteins (MAPs) and molecular
motors.[5,6] In order to fulfill a large diversity of functions, cells
build microtubule arrays that differ in organization and dynam-
ics (reviewed in ref. [7,8]). In general, dividing cells contain radi-
ally organized microtubules that are anchored through their mi-
nus ends to the centrosome (Figure 1a). In contrast, most differ-
entiated cells carry cell type specific, non-radial arrays (Figure 1b).
As microtubules are central for properly execute various essential
features in virtually every cell, failure to accurately organize the
microtubule cytoskeleton leads to diverse pathologies including
genomic instability, cancer, and various degenerative and devel-
opmental disorders (reviewed in ref. [9–13]).
2. Microtubule Structure and the “Tubulin Code”
Despite fundamental breakthroughs in the regulation of micro-
tubule dynamics and organization in vitro, the spatio-temporal
regulation of microtubules in vivo—in particular during tissue
morphogenesis—has remained poorly defined. Diversity in the
organization and function of the microtubule cytoskeleton is pri-
marily achieved through variations in the primary sequence of
tubulin isotypes.[14] These differences in amino acid sequences
between individual tubulin isotypes affect two important aspects
of tubulin function: First, they alter the global structure of in-
dividual tubulin protein and in consequence global microtubule
properties. Second, such changes change the binding affinity of
various microtubule associated proteins (MAPs).
Genetic analyses have already provided unequivocal evi-
dence for isotype-specific functions in vivo.[15] For example,
the beta-tubulin isotype (𝛽Tub85D) is required for meiosis and
axoneme assembly in the Drosophila male germline,[16] while
the beta-tubulin isotype 𝛽VI (TUBB1) determines the final cell
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Figure 1. Organization of microtubule cytoskeleton (blue) in different cell types.
shape of platelets,[17] and the beta-tubulin isotype 𝛽III (TUBB3)
yields neural migration in mice (reviewed in ref. [18]). While
the molecular mechanisms of isotype-specific regulation of
microtubule function is not fully understood, in vitro studies
with purified recombinant tubulin demonstrated isotype specific
polymerization dynamics.[19–21] Hence, as microtubule dynamics
is essential for basic cellular processes (e.g., division, motility,
and differentiation), the regulation of isotype expression directly
influences these processes. Indeed, in various cancers the
expression of tubulin isotype is altered, contributing to drug
resistance and disease aggressiveness.[9]
Another principal feature of 𝛼- and 𝛽-tubulin variations is
that sequence differences can be found predominantly in the
C-terminal tails, where most posttranslational modifications oc-
cur (reviewed in ref. [22]). Enzymes that introduce posttransla-
tional modifications are important for normal development and
perturbation in these proteins have been linked to several dis-
eases (reviewed in ref. [10,23]). This genetically encoded and
posttranslational generated heterogeneity at the level of individ-
ual tubulin proteins—coined the “tubulin code”—has the poten-
tial to modulate structural properties and functions of micro-
tubule such as the binding of MAPs and motor proteins.[24–28]
The most common posttranslational modifications include acety-
lation, glutamylation, glycylation, phosphorylation, and polyam-
ination, which are found at the C-terminal tails of both 𝛼 and
𝛽-tubulin. In addition, detyrosination/tyrosination and Δ2- and
Δ3-tubulin deletions occur, which only modify the C-terminal tail
of 𝛼-tubulin (reviewed in ref. [10,24,28]).
Microtubules in motile cilia and flagella have high levels of
glutamylation, acetylation, and glycylation.[29] Muscle micro-
tubules, in contrast, are detyrosinated and acetylated,[30] while
neurons contain axon-specific detyrosinated and acetylated
microtubules.[31] Currently, we still lack a precise mechanistic
understanding of the tubulin code. How exactly biochemical
modification relate to microtubule requirements? Glutamyla-
tion, detyrosination, and acetylation are all enriched in micro-
tubules subpopulations with long lifetimes that show resistance
to drug-induced depolymerization.[32–34] In contrast, acetylation
of 𝛼-tubulin lysine 40 (K40) increases their mechanical resilience,
allowing microtubules to comply with deformative forces with-
out breaking.[35] It was demonstrated that K40 acetylation alters
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interactions within the microtubule lattice, suggesting that bio-
chemical modification of microtubules could play an important
role in modulating global microtubule properties.[36] Moreover, it
was demonstrated in cardiomyocyte that detyrosination increases
the mechanical resistance to contraction via interactions with the
sarcomere, indicating its role in the contraction–relaxation cycle
of myocytes.[13,30] Finally, posttranslational modifications that af-
fect binding of MAPs can also change the mechanical properties
of microtubules.[28,37–39] Collectively, these studies demonstrate
that the tubulin code controls microtubule cytoskeleton at many
levels. Yet, how such regulatory mechanisms operate in vivo
remains unknown and is a major challenge for the future.
3. Generation of Forces by Microtubules
Recent findings demonstrate that tissue remodeling requires
physical forces generated either by the actomyosin or the mi-
crotubule cytoskeleton. While actomyosin is a well-established
force generator, microtubules have traditionally not been viewed
in this role (except during cell division). Yet, physiologically
relevant forces are generated by the microtubule cytoskeleton.
Microtubules can directly generate forces by polymerization and
depolymerization. The addition of a GTP-tubulin dimer or the
removal of GDP-tubulin dimer from the microtubule plus end
releases free energy (ΔG) on the order of 10 kB T (corresponds
to ≈4 pN) that can be used to perform mechanical work.[40]
When a growing microtubule encounters a barrier the addition
of new tubulin dimers will exert a pushing force on the barrier,
reminiscent of the Brownian ratchet described for actin.[41] Sim-
ilarly, a depolymerizing microtubule that remains connected to
a structure will pull the object (e.g., separations of chromosomes
during cell division). It is estimated that a single microtubule
(with 13 protofilaments) can generate a force of approximately 50
pN by polymerization or depolymerization,[5,42–44] respectively.
This is in stark contrast to earlier studies suggesting that a
single microtubule can only generate 4 pN.[45] In this study,
microtubule buckling was used to quantify pushing forces
against the barrier. While isolated microtubules buckle when
compressed by 4 pN, this also limits the maximum force that
can be generated by single isolated microtubules. Later studies,
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however, showed that microtubules within the cytoplasm are
reinforced by the meshwork of other cytoskeletal components,
a property that allows them to resist compressive loads up to
100 pN.[46] This would allow to generate theoretical maximum
force that is more than ten times higher in living cells. In the
case of microtubule crosslinking/bundling, the generated force
increases linearly with the microtubule number.[47] Moreover,
it was measured that the spindle, a dense radial array of micro-
tubules that is crosslinked with motor and non-motor proteins,
can generate forces of up to 700 pN.[43,48,49] Thus, while we still
lack precise measurements of forces generated by microtubules
in vivo, these studies clearly establish them as relevant, yet
under-studied force-generating components of the cytoskeleton.
Notably, processive molecular motor proteins associated with
microtubules can use the free energy that is released by hydrol-
ysis of ATP to generate forces to push or pull microtubules. The
sliding of microtubule pairs was demonstrated for plus end and
minus end motor proteins. Kinesin-5 will push apart two micro-
tubules that are aligned antiparallel when walking towards their
plus ends.[50] Similar observations were made for the minus end
directed motor proteins dynein[51] and members of the kinesin-
14 family.[52] Dynein can also pull on microtubule by moving
laterally on microtubule lattice, while being attached to the cell
cortex, thus generating pulling forces that are crucial for spindle
and centrosome positioning in cells.[53] Individual motor pro-
teins generate forces ranging from 1 to 10 pN. Hence, as longer
overlaps can bind multiple motor proteins, the final pushing and
pulling forces will scale correspondingly.[54] Finally, force gener-
ation was also attributed to diffusible microtubule crosslinkers
lacking intrinsic motor activity. In this motor independent force-
generating mechanism, the diffusion within a confined space
between two microtubules generates a pressure that yields micro-
tubule sliding,[55] establishing a rich variety of mechanisms exert-
ing microtubule-based forces via interaction to auxiliary proteins.
Curiously, not only the active generation of forces, but also
the mechanical properties of microtubules play a role in cell me-
chanics. Microtubules have the same elastic modulus as actin fil-
aments (on the order of 1 GPa), however they are 100 times stiffer
than actin with a bending rigidity of ≈2 × 10−23 Nm2 .[56,57] This
corresponds to a persistence length of the order of millimeters,
what makes them crucial structural elements in a vast array of cel-
lular functions. As mentioned earlier, the measured microtubule
rigidity in vitro differs significantly to in vivo, since it depends
on their diameter. In addition, microtubules contain a varying
number of protofilaments, ranging from 8 to 17, which not only
changes their diameter, but also alters their stiffness (stiffness
scales with diameter).[58–60] Finally, they can also be bundled by
other proteins, further increasing their stiffness. For example, for
tightly cross-linked bundles that do not slide, the stiffness would
scale with the square of the microtubule number.[61] Strikingly,
the stiffness of two cross linked microtubules will increase 4-fold,
a drastic change that is consistent with a significant contribution
of microtubules to cell mechanics.
4. Microtubules in Cell Mechanics
Despite their favorable biophysical properties and their
widespread deployment in a large variety of cellular contexts, our
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understanding of the mechanical contribution of microtubules
to tissue formation is only now emerging. In the past years,
several studies demonstrated their mechanical contribution to
cell mechanics[46,62–69] and a tensegrity model was proposed,
suggesting that the ability of microtubules to withstand compres-
sion balance tensional forces in vivo (reviewed in ref. [70]). Yet, to
exert forces, or resist compression, requires not only rigid micro-
tubules but also a mechanical coupling to the cell boundary. Mi-
crotubules generally grow persistently in the cytoplasm, but once
they hit the cell cortex they transition from growth to shrinkage.
Moreover, microtubule plus ends are sensitive to compression-
induced catastrophes, which limits the load bearing capacity
necessary for their direct mechanical function.[71] It was thus pro-
posed that catastrophe rescue factors, which promote assembly,
could increase stability of microtubule plus ends at load-bearing
microtubule sites.[72,73] In vivo, microtubules are indeed associ-
ated with a number of plus-end-tracking proteins (+TIPs) that
accumulate at the growing end, where they regulate microtubule
dynamics in various way (reviewed in ref. [6,73]). End-binding
proteins (EBs), for instance, form a tip-tracking complex that
promotes MT dynamics and growth, while cytoplasmic linker
proteins (CLIPs) and CLIP-associated proteins (CLASPs) in-
crease microtubule polymerization rates and promote rescues.
Similarly, members of the kinesin-4 family,[6] and the recently
identified +TIP protein SLAIN2 inhibit catastrophe.[74] These
rescue factors are thus a pivotal part of the mechanism con-
trolling microtubule dynamics. Understanding the full extent
of their interaction with microtubules will be essential for
deciphering the direct role of microtubules in cell mechanics.
5. Microtubules as Driving Force of Epithelial
Morphogenesis
Over the last decade, the importance of the actin cytoskeleton
in morphogenesis has been shown for many tissues. The pic-
ture that has emerged from these studies is that actin, together
with myosin, forms contractile arrays that are key constituents
of different morphogenetic processes, ranging from epithelial
folding to cell intercalation and tissue convergence (reviewed in
ref. [75,76]). While these studies have established the importance
of actin-based mechanical forces, which are coupled across cell
boundaries via intercellular adherens junctions, the role of mi-
crotubules in cell shape changes and cell mechanics has only re-
cently emerged.[77–79] In the following section, I focus on recently
published works revealing new insights into the mechanical role
of microtubules in 2- and 3-dimensional remodeling of epithelial
tissues during morphogenesis.
5.1. Microtubule Mechanics is Required for Epithelial Folding
Epithelial folding is one of the fundamental morphogenetic pro-
cesses that shape organs and tissues (reviewed in ref. [80]). Fold-
ing is driven by coordinated cell shape changes, normally starting
with the apical constriction, followed by cell shortening and basal
expansion. If cells preserve they volume, then these changes
cause global folding of the tissue. Both these steps have been
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Figure 2. Organization of microtubules during epithelial cell reshaping. a) Schematic drawing of the Drosophila gastrula indicating the organization
of non-centrosomal meshwork (blue) along the apical/basal axis (A/B) supporting the apical surface of the cell (red arrows). Patronin (green dots),
which stabilizes microtubule minus ends, is localized to the apical cortex just prior to emergence of the apical dome. b) Schematic of Drosophila wing
epithelium showing patterning of the microtubule cytoskeleton (blue) along the proximal/distal axis (P/D) in developing pupae and the direction of
microtubule-based forces (red arrows) from ref. [78].

strongly associated with actomyosin-based contractility (reviewed
in ref. [81]), while microtubules were proposed to have only sup-
porting functions, such as stabilization of the actomyosin.[82,83]
Intriguingly, a recent study identified the non-centrosomal mi-
crotubule network as main force generator that directs folding
of the epithelial sheet on the dorsal side of the gastrulating
Drosophila embryo.[77] In these epithelial cells, myosin contractil-
ity is low and can thus not explain the occurring changes in cell
shape. Instead, the authors tested whether microtubules control
cell shortening needed for tissue folding. Strikingly, they demon-
strated that the cell shape relies on stiff microtubules that gener-
ate pushing forces to shape the apical cell surface (Figure 2a).
Moreover, they showed that sliding of anti-parallel microtubules
via dynein[51] was used to further increase microtubule generated
forces. Notably, microtubules that line the inner apical side of
cells are non-centrosomal microtubules, patterned by the minus-
end stabilizing protein Patronin (homolog of the mammalian
CAMSAP proteins),[84] which is localized to the apical cell cor-
tex via the Baz/Par3-Par6-aPKC complex. Consistently, sequen-
tial downregulation of Par1 protein, which was previously shown
to trigger cell shortening and tissue folding causes redistribution
of Patronin.[85] Finally, the same study showed that Patronin also
recruits Katanin, a microtubule-severing enzyme, thus facilitat-
ing microtubule remodeling[86] and weakening of microtubule
generated forces. Together, these findings are consistent with
the tensegrity model, whereby microtubule cytoskeleton initially
generates forces that shape epithelial cells and consequential re-
modeling of microtubules that disturbs force balance along the
apico-basal axis leading in cell shortening during gastrulation.
5.2. Microtubule Mechanics Directs Epithelial Elongation
Remodeling within the plane of the tissue, which is essential for
epithelial elongation, is another fundamental morphogenetic
process controlled by microtubule dynamics. Tissue elongation
can be achieved by different cell behaviors, including cell shape
changes, polarized cell intercalation, oriented cell division, and
collective cell migration.[87–89] As above, recent study demon-
strate a direct mechanical role of microtubules in this process.[78]
Using the developing Drosophila wing the study revealed that pat-
terned non-centrosomal microtubules generate pushing forces
to elongate individual cells in a coordinated manner.[78] During
pupal wing development, apical junctions become the major non-
centrosomal microtubule-organizing center that organize micro-
tubules into a planar polarized apical microtubule network.[90,91]
The junctional microtubule organizing centers are located on
the proximal and distal sides of each columnar epithelial cells,
and are globally aligned along the evolving proximal-distal (PD)
axis (Figure 2b). The resulting trans-cellular microtubule net-
work undergoes coordinated rearrangements concomitant with
tissue remodeling including cell elongation,[4,90,92] suggesting a
role in this process. Strikingly, additional experiments demon-
strated that during epithelium elongation individual cells stayed
mechanically autonomous and did not rely on tissue extrinsic
forces for cell shape changes. These findings are relevant, as
they demonstrate that forces required for initial cell elongation
are generated within individual cells.[78] Interestedly, the distri-
bution and contractility of myosin in these cells is low, like in
dorsal cells during gastrulation.[77] Hence, the study revealed
that microtubules in these cells are stiff and bear compressive
forces that originate from cell-endogenous microtubule polymer-
ization. Together, these results provide evidence that physical
forces based on global patterning of microtubules contributes
to cell mechanics to coordinate cell elongation during tissue
rearrangements.
Yet how are microtubules aligned on the tissue level, a core
requirement to coordinate forces during morphogenesis? No-
tably, patterning of microtubules in the wing tissue depends
on the conserved Fat planar cell polarity (Ft–PCP) signaling
pathway.[90,92,93] The Ft–PCP consists of the atypical cadherins
Fat (Ft) and Dachsous (Ds), as well as the Golgi resident protein
Four-jointed (Fj).[94–98] Ft and Ds localize to adherens junctions,
where they form transcellular heterodimers. As Fj and Ds are
expressed in opposing gradients across tissues, they orient the
polarization of Ft–Ds heterodimers along the same tissue axis

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(reviewed in ref. [98–102]). Ft–PCP signaling in wing cells is
required for both, polarized nucleation of microtubule minus
ends and stabilization of microtubule plus ends at junctions
oriented along the extended cell axis.[78] The dual function of
the Ft–PCP can be explained by polarized distribution of Ft–Ds
heterodimers, where one cadherin acts as a microtubule minus
end organizing protein while the other serves as effector of plus
end proteins. Importantly, the increased stability of microtubule
plus ends at the adherens junctions is a key factor for increased
microtubule load bearing capacity, a potential mechanism by
which microtubules contribute to cell mechanics.[71] Moreover,
Ft–PCP mutant animals, with constant microtubule number but
perturbed organization, show impaired cell elongation and an ab-
normal rounded wing shape,[4,78,103,104] thus further supporting
the central role of microtubule mechanics in tissue elongation.
6. Conclusions and Outlook
The last decade led to a sharp rise in evidence for mi-
crotubules as central structural components that counter
compression,[30,46,62,64–69,77,105] thus contributing to the mechan-
ical state of epithelial tissues.[77,78] Yet, to date our understand-
ing of microtubule mechanics is strongly influenced by insights
gained from in vitro models that do not reveal the complexity
of mechanisms controlling the interplay between microtubules
and their effectors (e.g., motor proteins, MAPs, modification en-
zymes). Accordingly, a large number of fundamental questions
remain unanswered. For instance, while current work has estab-
lished microtubules as force generators, it does not accommo-
date the fact that biochemical differences exist between micro-
tubules, leading to different temporo-spatial distributions of mi-
crotubule mechanical properties within the same tissue. More-
over, we still lack the knowledge on contribution of MAPs and
motor proteins to generation of forces within microtubule cy-
toskeleton during morphogenesis. Also, how are microtubules
organized within cells, and how do they switch between differ-
ent types of architecture—especially in developing tissues that
are still proliferating? How do these mechanisms crosstalk dur-
ing morphogenesis? For instance, the recent insight into the me-
chanical properties of the epithelium tissue during Drosophila
cellularization revealed that it undergoes microtubule depend-
ing softening.[79] Yet how this is achieved remains elusive. These
modifications are relevant, as changes in tissue mechanical prop-
erties could significantly impact the sequential remodeling of the
tissue, as in softer environment the propagation of the strain
would be weakened, limiting the deformation to local side and
not affecting other process within tissue. Lastly, the hallmark of
tissue development is collective cell behavior, yet it remains elu-
sive how the accurate integration of locally produced mechanical
forces into a global tissue force pattern is accomplished.[106]
To tackle these fundamental questions requires the contin-
ued development of new biological, chemical, and physical ap-
proaches that will allow accurate quantification of mechanical
parameters of the microtubule cytoskeleton in vivo. While a chal-
lenging task, these future studies will provide new concepts that
can uncover novel functions for microtubules and explain both
normal development and physiology, and disease states where
force coordination has gone awry.
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Acknowledgements
The author would like to thank the members of the Matis lab for critical
reading of the manuscript. This work was supported by funds from the
German research foundation DFG (EXC-1003, SPP-1782, MA 6726/3) and
from the IZKF (Mat2/019/16).
Conflict of Interest
The author declares no conflict of interest.
Keywords
cell mechanics, cell shape changes, microtubules, tissue development
Received: December 12, 2019
Revised: February 12, 2020
Published online: April 3, 2020
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