REVIEW ARTICLE
Cytoskeleton, October 2013 70:590–603 (doi: 10.1002/cm.21130)
C
V 2013 Wiley Periodicals, Inc.
How Filopodia Pull: What We Know About the
Mechanics and Dynamics of Filopodia
Thomas Bornschl€
ogl*
Institut Curie, Laboratoire, Physico-Chimie UMR CNRS 168, 11 Rue Pierre et Marie Curie, 75005, Paris, France
Received 16 May 2013; Revised 31 July 2013; Accepted 1 August 2013
Monitoring Editor: Laura Machesky
In recent years, the dynamic, hair-like cell protrusions
called filopodia have attracted considerable attention.
They have been found in a multitude of different cell
types and are often called “sensory organelles,” since
they seem to sense the mechanical and chemical envi-
ronment of a cell. Once formed, filopodia can exhibit
complex behavior, they can grow and retract, push or
pull, and transform into distinct structures. They are
often found to make first adhesive contact with the
extracellular matrix, pathogens or with adjacent cells,
and to subsequently exert pulling forces. Much is
known about the cytoskeletal players involved in filopo-
dia formation, but only recently have we started to
explore the mechanics of filopodia together with the
related cytoskeletal dynamics. This review summarizes
current advancements in our understanding of the
mechanics and dynamics of filopodia, with a focus on
the molecular mechanisms behind filopodial force
exertion. V 2013 Wiley Periodicals, Inc.
C with deprived filopodia migrate in a disoriented manner
Key Words: filopodia; actin; retrograde flow; force; mem-
brane tension
Introduction—The Biological Role of
Filopodia
F ilopodia have been observed in a multitude of different
cell types, both in vivo and by using cell cultures on 2D
and 3D substrates in vitro. Under these experimental condi-
tions, filopodia are often the first component of the cell to
establish contact with extracellular cues, and they are able
to probe a large area surrounding the cell due to their
dynamics and hair-like shape. This makes filopodia perfect
“cell antennae” and indeed in many instances the primary
biological role of filopodia seems to be the sensing of
*Address Correspondence to: Thomas Bornschl€ogl, Institut Curie,
Laboratoire Physico-Chimie, Centre de Recherche, 26 Rue
d’Ulm, Paris F-75248, France. E-mail: bornschl@ph.tum.de
Published online 3 September 2013 in Wiley Online Library
(wileyonlinelibrary.com).
䊏 590
external mechanical and chemical cues [Mattila and
Lappalainen, 2008; Mellor, 2010]. The most extensively
studied filopodia are those protruding from the neuronal
growth cone (See Fig. 1A for a schematic drawing). These
were initially discovered in the late 19th century by Ramon
y Cajal in fixed nervous tissue and were later observed in
vitro by Ross Harrison, who used the first tissue culture of
dynamic neuron explants [Cajal, 1890; Harrison, 1910;
Keshishian, 2004; Meldolesi, 2011]. Today, there is a grow-
ing body of evidence that growth cone filopodia are
involved in the sensing of chemotactic signals leading to the
directed, path-finding growth of an axon [Gallo and
Letourneau, 2004; Geraldo and Gordon-Weeks, 2009;
Koleske, 2003]. For instance, it was shown that growth
cones turning toward a chemoattractant, exhibit an
increased number of filopodia on the side that is facing the
attractant [Gundersen and Barrett, 1980; Zheng et al.,
1996]. Additionally, Cytochalasin-treated growth cones
[Bentley and Toroian-Raymond, 1986]. The physical con-
tact of a single filopodium with a high affinity substrate,
such as a guidepost neuron or a bead coated with nerve
growth factor is sufficient to change the path of a growth
cone [O’Connor et al., 1990; Gallo et al., 1997]. Their
ability to sense guidance cues [Davenport et al., 1993;
Shafer et al., 2011], coupled with their ability to apply trac-
tion forces on the substrate via a frictional slippage mecha-
nism [Chan and Odde, 2008], would allow the filopodium
to act as a steering mechanism for neuronal growth. Many
of our insights into growth cone guidance are gained from
in vitro cell culture experiments, but nonmammalian model
systems or the extraction of mammalian cortical slices allow
verification of these findings in vivo [Kalil et al., 2011].
In the nervous system, filopodia can be involved in other
specialized tasks aside from growth cone guidance. For
example, dendritic filopodia have recently been shown to
play a role in the sensation of touch in specialized sensory
neurons of Drosophila larvae [Tsubouchi et al., 2012]. Strik-
ingly, filopodia can also mature into different structures,
they are the precursors of presynaptic boutons at the initial
stage of synaptogenesis and they can become spines or

Fig. 1. Filopodia and forces in biological systems. A) Sketch
of a migrating growth cone on a 2D substrate. The growth cone
is turning toward the right, e.g., due to the gradient of a chemo-
attractant. The filopodia exert traction forces (F) on the substrate
and show asymmetric distribution before turning; more filopodia
are extending toward the chemoattractant. B) Drawing of a Dro-
sophila embryo during the stage of dorsal closure. Filopodia span
the gap between the two opposing epithelial sheets at the position
of zipping (see black square and bottom picture for zoom). Zip-
ping forces, together with selective adhesion to matching partner
cells, are important for proper alignment. C) Sketch of well-
adhered cells cultured on a 2D substrate. Filopodia-like cell–cell
bridges between the infected upper cell and a noninfected cell
can transport virus particles (red circle). Bacteria, such as Shigella,
can contact the tips of filopodia and induce their retraction in
order to get pulled toward the cell for invasion (red ellipse). In a
similar way, macrophages use filopodia to detect and pull patho-
gens toward the cell body, where phagocytosis occurs.
dendrites [Heiman and Shaham, 2010; Hotulainen and
Hoogenraad, 2010; Menna et al., 2011].
Besides their importance within the nervous system, filo-
podia also play a role in cell–cell adhesion of epithelial tis-
sues, for example during morphogenesis or wound healing.
In the situation of wounded epithelia, the implicated cells
often produce an actomyosin cable surrounding the orifice,
which then closes. Depending on the organism and cell
type, filopodial and lamellipodial protrusions can be
observed in the leading edge cells [Garcia-Fernandez et al.,
2009]. Filopodia seem to be implicated in making first con-
tacts with the opposing cell fronts, where they might serve
as precursors for the formation of mature cell–cell junctions
[Vasioukhin et al., 2000; Brevier et al., 2008]. In wounded
epithelia, filopodia can also act as long-range sensors for
cytokines, such as epidermal growth factor [Lidke et al.,
2005]. This cytokine is upregulated at the site of the wound
and leads to enhanced cell migration to support healing.
CYTOSKELETON
A similar situation arises during dorsal or ventral closure
in developing embryos of different organisms. In vivo con-
focal microscopy showed filopodia in Drosophila embryos
during dorsal closure, where they were implicated in the
zipping of the two opposing leading edge cells [Jacinto
et al., 2000] (See Fig. 1B for a schematic drawing). These
filopodia control the accurate alignment of the opposing
epithelial sheets by creating mutually exclusive contacts
between matching partner cells [Millard and Martin,
2008]. Filopodia have also been observed in C. elegans dur-
ing ventral closure and in migrating muscle cells [Williams-
Masson et al., 1997; Raich et al., 1999; Viveiros et al.,
2011], as well as during sea urchin gastrulation [Miller
et al., 1995]. In all these situations, filopodia seem to fulfill
a sensory and adhesive function toward specific binding
partners. This function, together with the build up of
mechanical force and cell internal signaling, could promote
the proper positioning of the cells within the developing
embryo [Hutson et al., 2003; Lecuit et al., 2011].
Filopodia have been shown to sense signaling molecules a
large distance away from the cell body. Filopodia-like struc-
tures, implicated in cell–cell communication in inverte-
brates, were first observed in the Drosophila wing imaginal
disc and were named cytonemes [Ramirez-Weber and
Kornberg, 1999; Gradilla and Guerrero, 2013]. Cytonemes
can orient toward the morphogen [Hsiung et al., 2005] and
are specialized for the sensing of specific signaling pathways
[Roy et al., 2011]. Highly dynamic filopodia have recently
been shown to be critical for tissue patterning in Drosophila.
Here, the physical contact of filopodia can transmit Delta-
Notch signaling over long distances, which explains how
the spacing of bristles on the Drosophila notum is con-
trolled [De Joussineau et al., 2003; Cohen et al., 2010].
Recently, a similar long-range sensing mechanism of the
morphogen sonic hedgehog has been observed in the verte-
brate limb bud of chick embryos [Sanders et al., 2013].
Similar filopodia-like cell–cell bridges have been impli-
cated in the transport of various cargoes ranging from Ca21
to entire organelles and are often called tunneling nano-
tubes in this context [Rustom et al., 2004; Abounit and
Zurzolo, 2012; Sherer, 2013]. Pathogens can hijack filopo-
dia and filopodia-like cell–cell bridges (See Fig. 1C for a
schematic drawing). For example, viruses have been
observed surfing on filopodia-like cell bridges from an
infected cell toward a noninfected cell, thus explaining why
viral infection is more efficient when cells have physical
contact [Lehmann et al., 2005; Sherer and Mothes, 2008].
Invasive bacteria can hijack filopodia of epithelial cells to
approach the host cell before infection occurs [Romero
et al., 2011]. Similarly, macrophages have been shown to
use filopodia as precursors for phagocytosis. Their filopodia
can capture latex beads [Koerten et al., 1980], as well as
beads covered with bacterial surface proteins [Kress et al.,
2007; Zidovska and Sackmann, 2011], and pull them
toward the host cell, where phagocytosis can occur.
Bornschl€ogl 591 䊏
Fig. 2. Organization of the actin cytoskeleton in different cells. A) Electron microscopy (EM) of a growth cone from a differenti-
ated B35 rat neuroblastoma cell [Korobova and Svitkina, 2008]. The image shows the typical, fan-like organization with filopodial
actin bundles that are deeply embedded in the dendritic lamellipodial actin network. B) EM of the leading edge of the lamellipodium
of a B16F1 mouse melanoma cell. The protruded filopodium is rooted at its base within the lamellipodial actin network. C) EM of
the same cell type showing two joining actin bundles forming a filopodial k-precursor. The bundled filaments splay apart at the filo-
podial base and are again intimately interwoven with the dendritic lamellipodial network. From Svitkina et al. [2003].

The different filopodia listed above fulfill highly special-
ized tasks. However, they share similarities in their structure
and they are often built up by the same basic components
[Faix et al., 2009]. Thus, they likely use a limited set of
molecular core components together with an additional,
specific molecular machinery that allows them to fulfill
their sensory tasks [Gupton and Gertler, 2007; Abounit
and Zurzolo, 2012; Gradilla and Guerrero, 2013]. A com-
mon function of growth cone, macrophage, and epithelial
filopodia could lie in the sensing of specific binding part-
ners with a subsequent adhesion and build up of retraction
force. While we have a rather good understanding of the
basic cytoskeletal players that comprise filopodia, we have
only recently started to explore how these structures exert
forces. In this review, I will summarize experiments address-
ing these questions.
The Structure of Filopodia
Since their first observation with light microscopy more
than a 100 years ago [Cajal, 1890; Meldolesi, 2011],
improvements in microscopy techniques have allowed
researchers to gain insight into the molecular organization
of filopodia. A huge step forward was the invention of elec-
tron microscopy, together with cell fixation techniques that
allowed “finger-like processes” with a diameter of only
200 nm and length of several lm at the leading edge of
migrating cells on 2D substrates to be resolved [Porter
et al., 1945]. Although atomic force microscopy can be
used to visualize filopodia of living cells [Parpura et al.,
1993], electron microscopy allows to resolve the cytos-
keletal organization of filopodia. Figure 2A illustrates the
typical, fan-like cytoskeletal organization of a neuronal
growth cone with protruding filopodia [Bridgman and Dai-
ley, 1989; Schaefer et al., 2002; Korobova and Svitkina,
2008]. Electron microscopy has shown that the filopodial
core is made up of 15–30 tightly packed actin filaments,
which can exhibit a dense protein complex at the tip [Small
and Celis, 1978; Lewis and Bridgman, 1992]. In a 2D envi-
ronment, filopodial filaments are observed in different cell
types to be deeply rooted in the sheet-like lamellipodia
from which they can protrude [Pollard and Borisy, 2003;
Small and Resch, 2005]. The actin filaments at the filopo-
dial root can be intimately interwoven with the adjacent
lamellipodial meshwork (See Figs. 2B and 2C for the struc-
tural organization of the filopodial=lamellipodial interface
in B16-F1 mouse melanoma cells) [Svitkina et al., 2003].
In the lamellipodium, the branched actin network is organ-
ized in a polarized fashion, with actin filaments pointing
with their fast-growing barbed end toward the leading edge
[Small et al., 1978]. The polarity of an actin filament is
usually identified via the addition of molecular motor
heads, showing a polar decoration of the filament. Recently,
this polarity has been observed directly via image analysis of
electron tomographs of Swiss 3T3 cell lamellipodia [Narita
et al., 2012].
Filopodia can also protrude from cellular locations other
then the lamellipodium. For example, they can be found at
the apical or dorsal cell surface of cells cultured on 2D sub-
strates [Bohil et al., 2006; Planchon et al., 2011] and they

䊏 592 How Filopodia Pull CYTOSKELETON

can protrude from the cellular actin cortex as it can be seen in
situ [Fraccaroli et al., 2012]. The actin cortex is a 100-nm
thin, isotropic and contractile actin network that is situated
directly behind the plasma membrane [Salbreux et al., 2012].
The constituent actin filaments are mostly aligned parallel to
the membrane, but a few short perpendicular filaments have
also been observed [Morone et al., 2006]. In 2D cultures, filo-
podia can still protrude from cells with depleted lamellipodia
[Steffen et al., 2006; Gomez et al., 2007; Korobova and Svit-
kina, 2008; Nicholson-Dykstra and Higgs, 2008; Sarmiento
et al., 2008]. In this scenario, filopodia can form at the edges
of concave actin filament bundles that are arranged parallel to
the plasma membrane [Steffen et al., 2006], which might
resemble the geometry of cortically anchored filopodia. How-
ever, most structural studies on filopodia are done with cells
on 2D substrates, where they are rooted within the lamellipo-
dium, and thus little is known about the 3 dimensional ultra-
structure of the cell cortex and how filopodia are anchored
within [Ben-Harush et al., 2010].
Filopodia can form from the polarized lamellipodial actin
network by two proposed mechanisms, referred to as the
“convergent elongation model” and the “de-novo nuclea-
tion model” [Faix et al., 2009; Yang and Svitkina, 2011]. In
the first model, the branched filaments in the lamellipo-
dium, that are formed via Arp2=3 complex-mediated nucle-
ation, make k-shaped precursors at the leading edge [Small
et al., 1998; Svitkina et al., 2003; Yang and Svitkina, 2011]
and become crosslinked by fascin [Vignjevic et al., 2006]
(See Fig. 2C for an k-shaped precursor). In the “de-novo
nucleation model,” a parallel actin bundle is newly formed
and further polymerized at the leading edge of the lamelli-
podium via the action of e.g., formins [Faix and Rottner,
2006; Faix et al., 2009; Mellor, 2010]. In both models, the
filopodia formed must contain a bundle of polarized actin
filaments, pointing with their fast-growing ends toward the
tip of the filopodium, as observed experimentally [Lewis
and Bridgman, 1992]. Within the filopodial shaft, actin fil-
aments can be resolved without disruption throughout the
filopodium (See Fig 2) [Lewis and Bridgman, 1992]. It is
important to note that the fixation techniques used for elec-
tron microscopy might lead to slight alterations of the
observed actin structures [Small et al., 2008]. For example,
if the plasma membrane is removed with Triton before fixa-
tion and negative staining, filopodial actin filaments can
show gaps in between themselves and appear as wave-like
structures [Lewis and Bridgman, 1992]. In addition, parts
of the filopodial actin core are membrane-anchored, so
removing the membrane will likely disturb the related
structural features. Cryo-electron tomography circumvents
this problem by rapidly arresting the cellular structure in its
functional state, thus allowing insights into the actin-
membrane interface on a molecular level [Ben-Harush
et al., 2010].
Filopodia from most cell types are structurally very simi-
lar, showing a crosslinked actin bundle of polarized, contin-
CYTOSKELETON
uous filaments, as shown in Fig. 2B. One exception from
these conventional filopodia is the Dictyostelium filopo-
dium, which was recently visualized with intact membrane
by cryo-electron microscopy [Medalia et al., 2007]. In these
cells, the actin filaments within the shaft were mostly
aligned parallel to the filopodial axis but showed only an
average length of 200 nm, much shorter than the observed
1-lm long filopodia. Additionally, short actin filaments
were observed at the base of these filopodia. These filaments
are linked to each other at various angles and are not deeply
rooted in the cortical actin network [Medalia et al., 2007].
Another exception is the dendritic filopodium, the precur-
sor of dendritic spines [Hotulainen and Hoogenraad, 2010]
which has recently been shown to contain a small fraction
of actin filaments pointing with their slow-growing end
toward the filopodial tip [Korobova and Svitkina, 2010].
Additionally, immunostaining showed the unusual presence
of the actin-branching Arp2=3 complex and of myosin II in
the filopodial shaft, while the usually abundant cross-linker
fascin was absent.
The structure of filopodia might not only depend on the
specific cell type, but it might also change in correlation
with the dynamic state of the filopodium. For example, in
Dictyostelium, growing filopodia appeared straight and
firmly filled with actin, while retracting filopodia appeared
often bent and contained an almost disassembled actin core
[Medalia et al., 2007]. A recent study, using live cell imag-
ing correlated with electron tomography on B16-F1 mouse
melanoma cells, showed that retracting filopodia contained
a disintegrated actin bundle in correlation with the presence
of the actin-depolymerizing factor cofilin [Breitsprecher
et al., 2011]. In contrast, growing filopodia of the same
cells showed the conventional, tightly packed and parallel
actin bundle with no cofilin present.
The Dynamics of Filopodia
Different proteins regulate filopodial formation, mainte-
nance and dynamics: proteins that positively control actin
polymerization, such as formins [Peng et al., 2003; Romero
et al., 2004; Pellegrin and Mellor, 2005; Schirenbeck et al.,
2005; Mellor, 2010] and proteins of the Ena=VASP family
[Applewhite et al., 2007; Drees and Gertler, 2008] can
localize at filopodia tips. Proteins such as gelsolin [Lu et al.,
1997], capping protein [Mejillano et al., 2004], and EPS8
[Disanza et al., 2006; Menna et al., 2009] can negatively
control filopodia formation due to their ability to cap actin
[Menna et al., 2011]. Furthermore, membrane-bound pro-
teins from the I-BAR family, which sense and possibly
induce curved membranes, are implicated in filopodial for-
mation [Govind et al. 2001; Krugmann et al., 2001; Yama-
gishi et al., 2004; Millard et al., 2005; Ahmed et al., 2010;
Zhao et al., 2011]. Myosin X, a molecular motor, trans-
ports cargo toward the filopodial tip [Berg et al., 2000;
Zhang et al., 2004] and plays a role in filopodial formation
Bornschl€ogl 593 䊏

Fig. 3. The dynamics of filopodia. Reported dynamics of filo-
podia that are embedded in the rearward-moving lamellipodium
(thick grey arrow). The most commonly observed movement is
linear growth or retraction (I.). Growth or retraction is deter-
mined by the difference between actin polymerization speed at
the tip and retrograde flow in the filopodium. Sideward move-
ment of the filopodium (II.) can be explained via orthogonal
rearward flow in the lamellipodium, if the filopodial filaments
are tilted with respect to the cell edge. Filopodia can kink
within the actin shaft (III) or within the lamellipodium (IV).
Filopodia can also show scanning motion, turning around their
cell anchor point via angular rotations.
[Berg and Cheney, 2002; Watanabe et al., 2010], while
other nonconventional myosins might control membrane-
cytoskeleton adhesion [Nambiar et al., 2010].
Once formed, filopodia are dynamic structures that can
exhibit different modes of movement (See Fig. 3). For
example, they can show angular rotations around their cell
anchor point, which allows the filopodium to “scan” a large
area of the cell environment (Fig. 3, movement V)
[Albrecht-Buehler, 1976; Tamada et al., 2010; Zidovska
and Sackmann, 2011]. Filopodia that fold back onto the
cell in such a motion have been shown to become part of
lateral, contractile actin bundles within the lamellipodium
of migrating fish fibroblasts and B16 melanoma cells [Nem-
ethova et al., 2008]. They can also move laterally with
respect to the lamellipodial cell front (Fig. 3, movement II),
which can be explained by their tilted insertion within the
rearward-flowing lamellipodial actin network [Oldenbourg
et al., 2000]. The filopodial root, when embedded in the
lamellipodium, can kink [Nemethova et al., 2008] (Fig. 3,
movement IV), and a similar “jack-knife” mechanism
within the shaft of filopodia was observed in macrophages
and growth cone filopodia when plated on 2D substrates
(Fig. 3, movement III) [Sheetz et al. 1992; Kress et al.,
2007]. However, the most common motions of filopodia
are linear growth and retraction, which have been quanti-
䊏 594 How Filopodia Pull
fied in different cells types (See Fig. 3 movement I, Fig. 4A
and Table I).
The movement of a filopodium that is embedded in the
lamellipodium depends on lamellipodial dynamics. The
cytoskeletal dynamics of lamellipodia are well established in
a wide variety of cell types and show a continuous rearward
flow of the underlying actin network [Pollard and Borisy,
2003; Small and Resch, 2005]. Different proteins control
this retrograde flow. It is driven by the pushing action of
treadmilling actin filaments that polymerize against the
membrane at the leading edge and by contractile forces e.g.,
via myosin II at the lamellipodial base, where actin fila-
ments are depolymerized (See Fig. 4A) [Iwasa and Mullins,
2007; Lai et al., 2008; Bernstein and Bamburg, 2010;
Bugyi and Carlier, 2010].
Retrograde flow was also observed in filopodia. For
example, it can be observed indirectly, e.g., by analyzing the
rearward movement of material on growth cone filopodia
[Sheetz et al., 1992]. The first direct observations of actin
filaments moving rearward within growth cone filopodia
were made using photo-bleaching and photo-activation
microscopy on labeled actin [Okabe and Hirokawa, 1991;
Mallavarapu and Mitchison, 1999]. Quantification of these
dynamics showed that filopodial growth and retraction are
determined by the difference between actin polymerization
Fig. 4. Filopodial force exertion. A) Sketch of a linearly grow-
ing or retracting filopodium as shown in Fig. 3(I). In the lamel-
lipodium, the polymerization of actin at the leading edge (red
stripe) induces pushing forces against the cell membrane. This
action, together with the contraction and depolymerization of
actin (e.g., via myosin II and cofilin) at the lamellipodial base
(green area), leads to a continuous retrograde flow of the den-
dritic actin network. Since the filopodial and lamellipodial
structures are connected, friction could drive the retrograde flow
in the filopodium. Filopodia can then exert pulling forces using
the dynamics of the rearward-flowing actin (Fa), together with
inward forces arising from membrane tension (Fm). Filopodial
tips can exert pushing forces via actin polymerization at the tip.
B) Different geometries of filopodial adhesion. Reported pulling
forces are high (nN) if the filopodium exhibits a large adhesive
contact zone along the entire shaft. Reported pulling forces were
1003 smaller for geometries with decreased adhesive contacts,
such as contact only at the tip (from left to right).
CYTOSKELETON
 Table I. Retrograde Flow in Filopodia
Growth Retraction Retrograde
Filopodia=cell type Species (nm=s) (nm=s) flow (nm=s) Citation
Growth cone Aplysia, Chick, 17–170 17–170 10–100 Reviewed in Geraldo
filopodia Rat, Direct (photo-bleaching/ and Gordon-Weeks
and Mouse photo-activation of [2009]
labeled actin)
Embryonic cerebral Mouse 240 210 260 [Sheetz et al., 1992]
cortex filopodia Indirect (movement
of material)
Dendritic hippocampal Rat 0–17 0–17 20 [Tatavarty et al., 2012]
E18 filopodia Direct (PALM)
Cervix adenocarcinoma Human 135 84 (bacteria 22 [Romero et al., 2011]
(HeLa) filopodia induced) Direct
(photo-bleaching)
HeLa 100 10 15, 23 [Berg and Cheney,
Indirect (myosin 2002; Kerber et al.,
X movement) 2009]
HeLa 42 [Schelhaas et al., 2008]
Direct (photo-activation
and indirect virus
movement)
HeLa 5–50 [ur Rehman et al., 2012]
Indirect
(syndecan surfing)
Hela, epidermoid carcinoma Human 26, 18, 27 [Lidke et al., 2005]
cells (A431) Indirect (movement
and breast carcinoma of epidermal growth
cells (MCF7) factor coated
quantum dots)
Epidermal keratinocyte Human 40 13 20 vs. 42 [Schafer et al., 2010;
filopodia Direct (photo-bleaching Schafer et al., 2011]
of adhesive vs.
nonadhesive filopodia)
Kidney cell COS7 African green 70 10 30 [Watanabe et al., 2010]
filopodia monkey Indirect (myosin X
movement)
Cytonemes between African green 12 [Sherer et al., 2007]
kidney cells monkey Indirect
Cos-1 and XC and rat (virus surfing)
sarcoma cells
Embryonic kidney cell Human 30, 17 [Lehmann et al., 2005]
(HEK 293) Indirect
filopodia (virus surfing)
Quantifications of retrograde flow within filopodia of different cell types. Retrograde flow within filopodia of neuronal growth cones is well stud-
ied and is summarized in Geraldo and Gordon-Weeks [2009]. In addition, retrograde flow in filopodia of HeLa cells is now also well quantified
and was directly observed via photo-bleaching and photo-activation experiments. The measurement of e.g., rearward movement of myosin X or
viruses along filopodia can indicate the presence of retrograde actin flow indirectly and are also listed. Retrograde flow was also observed but not
quantified in filopodial shafts of B16F1 mouse melanoma cells [Applewhite et al., 2007] and filopodial filaments embedded in the B16F1 lamelli-
podia move backwards with approximately 30 nm=s [Vignjevic et al., 2006]. The table also summarizes observed average speeds of linearly grow-
ing or retracting filopodia.

rate at the tip and the speed of retrograde flow (Fig. 4A) switching from protrusion to retraction, correlated with a
[Mallavarapu and Mitchison, 1999]. In these experiments, change of the actin polymerization rate at the tip, while the
the majority of the changes in filopodial dynamics, such as retrograde flow speed stayed constant. This suggests that

CYTOSKELETON Bornschl€ogl 595 䊏

the tip-polymerization rate is the main parameter control-
ling filopodial dynamics [Mallavarapu and Mitchison,
1999]. Since then, photo-bleaching or photo-activation of
filopodial actin filaments has become a common tool to
quantify retrograde flow, which has led to a good under-
standing of cytoskeletal dynamics within growth cone filo-
podia [Geraldo and Gordon-Weeks, 2009]. Retrograde
flow was also observed in filopodia of other cell lines either
indirectly (e.g., via surfing of virus particles [Lehmann
et al., 2005]) or directly e.g., via photo-bleaching (See
Table I). In most cases reported so far, the speed of filopo-
dial retraction is slower than the internal retrograde flow
speed of actin. These results implicate retrograde flow,
together with reduced actin polymerization speed at the tip,
as the major mechanism for filopodial retraction, although
additional depolymerization of actin from the tip might
also occur [Breitsprecher et al., 2011]. While retrograde
flow seems to be a common feature of filopodia, its pres-
ence might depend on the particular cell line or the state of
development of the filopodium. For example, it was shown
that the retrograde flow observed in dendritic filopodia van-
ishes after maturation of the filopodium into a dendritic
spine [Tatavarty et al., 2012].
The Mechanics of Filopodia
In their natural environment, filopodia can make first con-
tact with other cells, the extracellular matrix or pathogens.
The adhesion to a substrate together with its underlying
actin dynamics allows the filopodia to exert pushing or pull-
ing forces. Surprisingly, relatively little is known about the
strength with which filopodia of different cells can pull and
how they exert forces. Recent experiments give first insights
into the working mechanisms of the filopodial pulling and
pushing machinery.
Pushing out the Membrane
The mechanics of filopodia are defined by the distinct
mechanical properties of its two basic constituents: the actin
bundle comprising the filopodial core and the surrounding
plasma membrane. In order to increase its length, the filo-
podial actin core has to grow inside the plasma membrane
tube that has to be pushed out. The plasma membrane is
constantly under tension [Gauthier et al., 2012; Diz-
Munoz et al., 2013], thus pushing out a membrane tube
requires force. The force needed to extrude empty plasma
membrane tubes from the cell e.g., with an optical trap are
in the range of 5–30 pN for different cell lines [Dai and
Sheetz, 1995; Sheetz, 2001]. Since the diameter of filopodia
is similar to the diameter of empty membrane tubes, cells
likely have to push against 10 pN in order to extend a
filopodium [Derenyi et al., 2002; Daniels and Turner,
2005; Nambiar et al., 2010]. This protrusion force can be
produced, for example, by the polymerization of actin at
the filopodial tip. In vitro experiments showed that a single
䊏 596 How Filopodia Pull
polymerizing actin filament is able to produce pushing
forces of 1 pN [Footer et al., 2007] and slightly higher
forces of 1.3 pN if its polymerization is assisted by formin
[Kovar and Pollard, 2004; Berro et al., 2007], which is
often found at filopodial tips. A crosslinked actin bundle
can resist buckling and therefore produce enough force for
filopodial growth via actin polymerization against the mem-
brane at the tip. However, dependent on the number of fila-
ments in the actin core, buckling and the diffusion of G-
actin toward the tip can be limiting factors for filopodia
outgrowth [Mogilner and Rubinstein, 2005; Atilgan et al.,
2006; Lan and Papoian, 2008]. By placing optically
trapped, nonadhesive beads in front of filopodia that are
protruding from growth cones of rat dorsal root ganglia,
pushing forces of 1–2 pN have been observed [Cojoc et al.,
2007]. This indicates that the internal actin core is able to
counterbalance membrane tension and to exert additional
small pushing forces on external objects.
It is important to note that actin may not be the only fac-
tor that can push out membrane tubes. Membrane binding
proteins containing an I-BAR domain could be able to
directly deform the plasma membrane [Suetsugu et al.
2006; Mattila et al., 2007; Ahmed et al., 2010; Zhao et al.,
2011]. For example, overexpression of IRSp53, a member
of the family of I-BAR domain proteins, was shown to
induce actin-free membrane tubes at the tips of filopodia
from B16F1 melanoma cells [Yang et al., 2009]. Although
these tubes might be mechanically unstable without subse-
quent support via the actin core, highly concentrated I-
BAR proteins could act as precursors for filopodial growth
via active deformation of the membrane.
Pulling Back With Force
In most physiological situations where filopodia have estab-
lished adhesive contact to extracellular substrates, as for exam-
ple during cell migration or wound healing, filopodia seem to
pull (See Fig. 1). Researchers have only recently started to
quantify the pulling forces exerted by filopodia. A first esti-
mate of filopodial pulling forces was obtained by observing
chick sensory growth cones that attached with their filopodial
tips to perpendicular neurites and subsequently pulled on
them [Heidemann et al., 1990]. In a prior publication, the
same group measured the forces that are needed to deflect
neurites using calibrated glass needles [Dennerll et al., 1989],
thus allowing them to estimate filopodial pulling forces to be
between 500 and 900 pN [Heidemann et al., 1990].
One potential means of quantifying forces exerted by
cells adhering to a substrate is traction-force microscopy.
For this technique, cells are plated on soft substrates with
well-calibrated elastic moduli containing marker beads that
allow recording of local deformations [Dembo and Wang,
1999; Schwarz and Gardel, 2012]. From the marker dis-
placements, local stress in the substrate can be calculated.
Using this technique, it was shown that filopodia from
CYTOSKELETON
cervical ganglion neurons from mice can exert maximal
pulling traction forces in the order of 1 nN on the substrate
[Bridgman et al., 2001]. Traction-force microscopy was also
used to show that retracting Dictyostelium filopodia exert
pulling forces via their distal tip portion [Iwadate and
Yumura, 2008]. The observed stresses were in the range of
0.3 kPa, which leads to an estimated pulling force of 100
pN, if we assume that the filopodium used a contact area of
1.0 3 0.2 lm2 to pull on the substrate.
Elastic, hair-like nanowires can also be used to estimate
pulling forces of filopodia. Human dermal foreskin fibro-
blasts were plated on substrates that exhibited islands of
“nanowire bushels.” Subsequently, electron microscopy was
used to show that filopodia attaching to nanowires are able
to bend these structures. By measuring the deflection of
nanowires, it was estimated that filopodia can pull with
forces of up to 2 nN [Albuschies and Vogel, 2013].
Filopodia from macrophages are known to bind with
their tips to bacteria in order to pull them toward the cell
body, where phagocytosis occurs. By replacing the bacteria
with an optically trapped bead, it was shown that these filo-
podia pull in a step-wise manner and pulling drastically
slowed down at relatively small forces of 15 pN [Kress
et al., 2007]. Additionally, similar measurements using
magnetic tweezers showed that macrophage filopodia stop
pulling and elongate with a force-independent, visco-elastic
behavior, if external forces between 20 and 600 pN are
applied [Vonna et al., 2007; Zidovska and Sackmann,
2011]. Similarly, filopodia from HeLa cells have been
shown to pull with their tips on optically trapped beads and
this pulling can be stalled at small forces around 15 pN
[Romero et al., 2012].
Interestingly, the pulling forces of filopodia listed above
exhibit a high degree of variability: the strongest reported
pulling forces in the nN range are similar to those exerted
by focal adhesions, highly specialized structures that trans-
mit forces to the extracellular substrate [Shemesh et al.,
2009; Wolfenson et al., 2009; Schwarz and Gardel, 2012].
In contrast, in other experiments filopodial pulling was
slowed down, inverted or stalled by forces of only 15 pN,
a force that could be produced by only a few molecular
motors. One remaining question is where these differences
come from. In the following, I will summarize first experi-
ments that can give hints to the answer.
How Filopodia Pull Back
Filopodial rearward force can arise from membrane tension
that leads to an inward force at the filopodial tip and from
active pulling via the retrograde flow of the actin cytoskele-
ton in the cortex. However, forces on the order of 1–2 nN
are unlikely to arise from membrane tension. Those forces,
that are on the order of 10 pN for empty plasma mem-
brane tubes [Sheetz, 2001], increase to a first approxima-
tion linearly with respect to the filopodial diameter
CYTOSKELETON
[Daniels and Turner, 2005]. Although the diameter of
retracting filopodia has been observed to increase [Heide-
mann et al., 1990], it would still be too small to entirely
account for forces in the nN range.
Therefore, it must primarily be the cytoskeleton that pro-
duces the reported high retraction forces. Filopodial actin
filaments could couple to the lamellipodial actin network
and use active rearward forces produced by lamellipodial
retrograde flow (Fig. 4A). One argument that points toward
high frictional coupling is the observation that filopodial
actin filaments flow backward together with the adjacent
lamellipodial network in growth cones, chick embryo fibro-
blasts, and B16F1 cells [Mallavarapu and Mitchison, 1999;
Medeiros et al., 2006; Vignjevic et al., 2006; Anderson
et al., 2008]. Frictional coupling would also explain the
contribution of myosin II to filopodial pulling. In migrat-
ing cells, myosin II is usually found in the lamella at the
rear of the lamellipodium (see green area in Fig. 4A) [Ponti
et al., 2004; Vicente-Manzanares et al., 2009; Wilson et al.,
2010], where it occasionally interacts with the roots of
deeply embedded filopodia [Anderson et al., 2008; Neme-
thova et al., 2008; Xue et al., 2010]. Similarly, in growth
cones, myosin II localizes at the rear of the lamellipodium
at the interface between P- and C-domains [Rochlin et al.,
1995; Medeiros et al., 2006]. Myosin II is a major driving
force behind retrograde flow [Cai et al., 2006; Vicente-
Manzanares et al., 2009], but it only accounts for half of
the retrograde flow in growth cones, with the other half
being produced by the pushing action of actin filaments
against the membrane at the lamellipodial leading edge
[Craig et al., 2012; Medeiros et al., 2006]. The contribu-
tion of myosin II to lamellipodial retrograde flow would
explain why filopodia from growth cones of myosin IIB
knock-out mice pulled less strongly on the substrate [Bridg-
man et al., 2001].
The observation that the speed of retrograde flow in the
filopodium decreases when they exert higher forces on the
substrate agrees with the model of frictional coupling. For
example, growth cone filopodia that are attached to soft
substrates show reduced speed of retrograde flow as com-
pared to stiff substrates [Chan and Odde, 2008]. This
observation was modeled with a stochastic “motor-clutch”
system that transduces filopodial traction forces with differ-
ent efficiency to the substrate in dependence on the sub-
strates’ stiffness. On soft substrates, filopodia pulled via a
load-and-fail behavior, transducing high traction forces that
correlated with a slow retrograde flow [Chan and Odde,
2008]. Similarly, in migrating keratinocytes it was shown
that retrograde flow in filopodia slowed down if they con-
tained premature, small focal complexes adhering to the
substrate [Schafer et al., 2010]. Interestingly, these small
focal complexes can mature later on into focal adhesions
[Nemethova et al., 2008; Schafer et al., 2010] that apply
traction forces to the substrate that depend on the speed of
lamellipodial actin flow [Gardel et al., 2008; Shemesh
Bornschl€ogl 597 䊏
et al., 2009; Wolfenson et al., 2009]. Ultimately, in order
to verify if friction between filopodial and lamellipodial
actin networks is responsible for filopodial force produc-
tion, experiments recording flow speeds in both actin struc-
tures under controlled loads would be necessary.
How can one explain the observed differences of maxi-
mal filopodial pulling forces that range between 20 and
2000 pN? One explanation would be different organization
of the cytoskeletal actin network adjacent to filopodial
roots. This organization depends on the cell type and on
the environment in which the cell is embedded [Baker and
Chen, 2012]. For cells spread on a 2D substrate, a large
contact zone between filopodial roots and the lamellipo-
dium would allow high friction and thus high pulling
forces. In contrast, less adhesive cells, cells with depleted
lamellipodia [Steffen et al., 2006] or cells embedded in a
3D environment [Baker and Chen, 2012] could show a dif-
ferent actin organization at filopodial roots with less fric-
tional coupling and direct interaction of molecular motors.
This could explain why filopodial retraction from less
adhesive macrophages, slows down against small forces of
only 15 pN [Kress et al., 2007]. However, the driving force
behind filopodial retraction in macrophages still needs to
be identified, since inhibition of myosin II and the use of
myosin V and myosin VI knock-outs continued to show
step-like retraction [Kress et al., 2007].
A second explanation for the observed dispersion in filo-
podial pulling forces is the adhesion strength between the
filopodium and the substrate (See Fig. 4B). The adhesion
strength depends on the type and total amount of the impli-
cated cell-adhesion receptors such as integrins [Letourneau
and Shattuck, 1989; Steketee and Tosney, 2002; Zhang
et al., 2004]. In the experiments that reported high pulling
forces, filopodia were able to adhere over a large area. For
example on 2D substrates used e.g., in traction-force micros-
copy, the filopodia can build adhesive contacts over its whole
length (Fig. 4B, left image) [Bridgman et al., 2001; Chan
and Odde, 2008; Schafer et al., 2010]. In contrast, in the
experiments reporting small filopodia pulling forces,
micrometer-sized beads were used as a substrate that only
contacts a small portion of the filopodium at the tip (Fig.
4B, right image) [Kress et al., 2007; Zidovska and Sack-
mann, 2011; Romero et al., 2012]. In this configuration it
was shown that the observed, average pulling forces can be
further decreased by decreasing the concentration of
filopodia-substrate links [Romero et al., 2012]. In the con-
text of a fibrillar 3D-environment, small dendritic extensions
of fibroblasts, neuron and glia cells have been shown to form
an entangled contact [Jiang and Grinnell, 2005; Sorkin
et al., 2009] and a recent publication models how the
increase of contact zone between filopodia and substrate can
lead to higher traction forces [Albuschies and Vogel, 2013].
It is important to note, that force-contributions from the
membrane tension become important if they get compara-
ble to actin-based forces produced in the cortex. This might
䊏 598 How Filopodia Pull
be the case for macrophages [Kress et al., 2007; Zidovska
and Sackmann, 2011] and it explains the dynamics of ster-
eocilia, a structure that shares some basic similarities with
filopodia. These rod-shaped membrane protrusions show
retrograde actin flow that is comparable to that observed in
filopodia, but with a 10003 lower speed [Rzadzinska et al.,
2004]. Friction at the base should therefore be much
smaller as compared to filopodia. A constant length of ster-
eocilia can then be accomplished if frictional forces at the
base counterbalance forces arising from membrane tension
[Prost et al., 2007].
In the future, exact quantification of these parameters,
together with the identification and quantification of the
molecular players controlling filopodial mechanics and
dynamics, will help to further decipher how filopodia
accomplish their impressive, multifunctional tasks.
Conclusions and Perspectives
Fluorescence microscopy techniques such as confocal and
speckle microscopy [Danuser and Waterman-Storer, 2006]
make it possible to record the dynamics of the filopodial
and lamellipodial actin cytoskeleton, while traction-force
microscopy can be used to probe filopodial mechanics
[Chan and Odde, 2008; Kraning-Rush et al., 2012]. In the
future, combinations of new high-resolution techniques,
together with force spectroscopy [Ahmed, 2011; Brenner
et al., 2011] will yield additional insights into the relation-
ship between the cytoskeletal dynamics and the mechanics
of filopodia. These techniques will shed new light on the
mechanisms filopodia employ in the regulation of force, and
how these adhesive structures differ from mature, mechano-
sensory focal adhesions [Chan and Odde, 2008; Plotnikov
et al., 2012]. The combination of live cell imaging and elec-
tron tomography will help to further decipher how the
structure of filopodia and protein content depend on their
actual dynamic state. A very important task will be to apply
our knowledge gained on 2D substrates to better understand
the function of the cells cytoskeleton in a more physiological
relevant 3D environment [Baker and Chen, 2012].
Acknowledgments
I thank D. Vignjevic and P. Bassereau for discussions and for
careful reading of the manuscript. Thanks to T. Svitkina for
providing the EM images. Thanks to M. Simunovic and M.
Bussonnier for proofreading and for help with Illlustrator.
I acknowledge the “Human Frontier Science Program” for
funding.
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