Volume 23 January 1, 2012
Polarity sets the stage for cytokinesis
Heidi Hehnly and Stephen Doxsey
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
ABSTRACT Cell polarity is important for a number of processes, from chemotaxis to embryo-
genesis. Recent studies suggest a new role for polarity in the orchestration of events during
the final cell separation step of cell division called abscission. Abscission shares several fea-
tures with cell polarization, including rearrangement of phosphatidylinositols, reorganization
of microtubules, and trafficking of exocyst-associated membranes. Here we focus on how the
canonical pathways for cell polarization and cell migration may play a role in spatiotemporal
membrane trafficking events required for the final stages of cytokinesis.
Cell polarity is a common feature of eukaryotic cells. A polarized cell
has a single axis of asymmetry, which can be thought of as “apical”
and “basal” (illustrated in Figure 1A) or “front” and “rear” (Figure
1B). This asymmetry encompasses a variety of cellular morphologies
that can differ among cell types in a single organism, as well as
within a single-celled organism such as Saccharomyces cerevisiae.
Cells within multicellular organisms also exhibit a distinct apical–
basal axis of polarity. One example is epithelial initiation, which oc-
curs during development and involves congression of mesenchymal
cells into aggregates that differentiate to form polarized apical–
basal cell monolayers. At the migratory stage, mesenchymal cells
set up a front–rear axis of polarity (Figure 1B). These polarity princi-
ples contribute to the higher-order organization of cell-based sys-
tems, such as shaping the embryo, wiring the developing nervous
system, maintaining and regenerating tissue, and developing the
immune response (reviewed in Nelson, 2009). Perturbations in cell
polarity contribute to a number of tissue pathologies. Particularly
striking examples include neuronal migration disorders (NMDs) such
as schizencephaly, porencephaly, and lissencephaly, which are
caused by defects in the polarized migration of neurons (for a review
on NMDs, see Valiente and Marin, 2010).
Specific sorting and maintenance of proteins to distinct mem-
brane domains ensures polarity formation. The defined distribution
of plasma membrane and cytoskeletal proteins in a polarized cell
requires signaling networks and protein complexes comprising the
Rho and Rab family GTPases, their downstream effectors, and polar-
ity complexes (Crumbs, PAR, and Scribble). Effectors include cy-
toskeletal proteins and vesicle-trafficking pathways. Vesicle traffick-
ing from the endocytic and/or exocytic membrane compartments
along a polarized cytoskeleton network is required for the establish-
ment of cellular polarity (reviewed in Nelson, 2009). This has been
elegantly illustrated in the budding yeast, S. cerevisiae, in which bud
growth is ensured by polarized secretion of Golgi apparatus–de-
rived membrane vesicles to cortical actin patches under the regula-
tion of Rho GTPases and polarity complexes at the bud tip (reviewed
in Chant, 1999; Irazoqui and Lew, 2004). In multicellular eukaryotes,
protein-sorting events occur at the endocytic pathway and Golgi
apparatus to ensure cell polarization (Nelson, 2009). For example,
plasma membrane–endocytic recycling is critical for maintaining po-
larized membrane protein residency to establish appropriate re-
sponses to stimuli such as nutrient internalization, junctional protein
sorting (e.g., E-cadherin), and ion channel recycling (Lock and Stow,
2005; Ducharme et al., 2006). Of interest, recent evidence shows
that vesicle trafficking is also required for the establishment of polar-
ized domains during cytokinesis, the final stage of cell division
Recent studies suggest that principles of cell polarity are engaged
during the process of cytokinesis. For instance, a migrating polarized
cell requires constant membrane addition via secretion at the lead-
ing edge to maintain “front–rear” polarity (Nelson, 2009), just as ab-
scission (the final stage of cytokinesis) requires membrane addition at
the cytokinetic bridge via secretion and endocytic vesicle delivery
(further discussed in the review by Prekeris and Gould, 2008, and
depicted in Figure 2). In both cases, membrane vesicles may act as a
platform for delivering essential regulators ensuring cell polarization.
Another similarity between cell polarity and cytokinesis occurs within
S. cerevisiae. In G1/S an actin patch is focused at the bud tip where
secretory vesicles are directed, and then the patch dissipates as the
bud becomes larger and the cell enters cytokinesis. Prior to spindle
Douglas R. Kellogg
University of California,
Received: Jun 14, 2011
Revised: Oct 17, 2011
Accepted: Oct 25, 2011
Address correspondence to: Stephen Doxsey (firstname.lastname@example.org).
Abbreviations used: aPKC, atypical protein kinase C; ARF6, ADP-ribosylation fac-
tor 6; FIP3 and FIP4, Rab11 family interacting protein; PAR6, partitioning defective
6 homologue alpha; PI(3,4,5)P3, phosphatidylinositol (3,4,5)-triphosphate; PI3Ks,
phosphatidylinositol 3-kinases; PI(4,5)P2, phosphatidylinositol (4,5)-bisphosphate;
PTEN, phosphatase and tensin homologue; SNARE, soluble N-ethylmaleimide-
sensitive fusion protein attachment protein receptor; WASP, Wiskott-Aldrich syn-
© 2012 Hehnly and Doxsey. This article is distributed by The American Society for
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able to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported
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“ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of
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MBoC | PERSPECTIVE
8 | H. Hehnly and S. Doxsey Molecular Biology of the Cell
disassembly and cell separation, polarized-actin patch proteins and
secretory vesicles are redirected to the mother bud neck, a structure
analogous to the cytokinetic bridge (VerPlank and Li, 2005). The
apparent importance of polarized vesicle trafficking to polarity and
the final stages of cytokinesis leads one to speculate about a con-
served underlying mechanism between the two processes. This no-
tion will be discussed and proposed throughout this essay.
During cell division the front–rear polarity of
phosphatidylinositols is reestablished in cytokinesis
Asymmetry in an epithelial, neuronal, or migrating cell is reflected in
its structural, molecular, and functional polarity. For example, in a
migrating cell the broad leading edge (front) of the cell defines the
direction of movement, and the more-focused rear trails behind.
When a migrating cell divides, it first rounds up, thus eliminating its
preexisting polarity. This involves vesiculating and dispersing sort-
ing compartments such as the Golgi apparatus and the endosomal
system. During cytokinesis, furrow ingression gives rise to the inter-
cellular bridge, a thin cytoplasmic connection between the two na-
scent daughter cells that is later resolved in the process of abscis-
sion. Each nascent daughter assumes an intracellular organization
roughly similar to an interphase cell, where the Golgi apparatus and
endocytic system have partially reorganized over the mother and
daughter centrosomes (Figure 2). At this time, cytokinetic cells have
started to reestablish front–rear polarity such that they need only to
sever the bond between them to gain the freedom to migrate.
The morphological front–rear polarity observed between migra-
tion and cytokinesis is further defined by molecular reorganization—
specifically, changes in phosphotidylinositol concentration within the
plasma membrane (Figure 1). However, little is known about how
lipid domain polarization occurs during polarization or cell division.
Possibilities include 1) remodeling of existing lipid domains by mem-
brane traffic (endocytosis, directed secretion); 2) cortical flow of spe-
cific phosphatidylinositols to and immobilization at a specific region;
and 3) targeting of lipid-modifying enzymes to a specific region. Cy-
tokinetic proteomic and RNA interference screens have led to the
identification of intracellular transport genes required for cytokinesis
(Echard et al., 2004; Skop et al., 2004) and subsequently for lipid
domain polarization. These genes included Rab GTPase family
members and inositol-modifying enzymes, such as phosphatidylinos-
itol 3-kinases (PI3Ks), which are Rab effectors (e.g., Rab5; Vieira et al.,
2003) that connect membrane traffic with lipid modification.
Cytokinesis is accompanied by polarized organization of phos-
phatidylinositols. For instance, phosphatidylinositol (3,4,5)-triphos-
phate (PI(3,4,5)P3) localizes to the plasma membrane near the spin-
dle poles. On the other hand, phosphatidylinositol (4,5)-bisphosphate
(PI(4,5)P2) predominantly localizes to the cleavage furrow and then
to the intracellular bridge between mother and daughter cells
FIGURE 2: Polarized membrane trafficking and membrane fusion at
the midbody during abscission. Secretory vesicles (green) and
Rab11-decorated endocytic recycling membranes (pink) undergo
directed motility to the cytokinetic bridge. However, the temporal
relationship between the two is unknown. Secretory vesicles (green)
are known to fuse (green line) with the plasma membrane adjacent to
the midbody. It is proposed that these vesicles transport to the
cytokinetic bridge, dock at the midbody by an exocyst-dependent
mechanism, and then fuse. Membrane addition is required for
abscission, but the role of this process is unknown. One possibility is
that secretory vesicles (green) or recycling endosomes (pink) bring
proteins needed for abscission. Another idea is that membrane fusion
is required to thin the bridge so that the fission step can occur as
efficiently as possibly.
FIGURE 1: Comparison of cellular polarity in cytokinetic cells,
polarized epithelial cells, and migrating cells. (A) In polarized cells the
exocyst (orange) is required for basolateral secretory-vesicle delivery
and apical endosomal membrane transport. The exocyst is localized
to the basal body/centrosome at the apical primary cilium. The apical
and basal sides are labeled. (B) In migrating cells the exocyst (orange)
is enriched at the leading edge and at recycling endosomes (lime
green) for polarized membrane fusion to occur that assists in cell
migration (arrow). The front and rear sides of the cell are labeled.
Phosphatidylinositols (pink and teal) are also polarized in cytokinetic
cells, polarized cells, and migrating cells. (C) During cytokinesis there
is polarized membrane traffic (arrow) of Rab11-decorated recycling
vesicles (lime green) to the cytokinetic bridge. The Rab11 recycling
endosome compartment (lime green) recruits a member of the
polarity complex, Crumbs, to the cytokinetic bridge (red). The exocyst
complex (orange) localizes to the midbody ring (black ring) and is
required for polarized membrane fusion during cytokinesis. The main
theme shared between polarized cells (A, B) and cytokinetic cells (C) is
that they coordinate the use of polarity proteins and polarized
membrane-trafficking pathways either to construct a polarized cell or
to complete cytokinesis.
Volume 23 January 1, 2012 Polarity and cytokinesis | 9
analogous to the rear of the migrating cell (Figure 1C; Janetopou-
los et al., 2005; Toyoshima et al., 2007). In a migrating cell, polarity
is established by local PI(3,4,5)P3 accumulation at the cell’s leading
edge (Figure 1B; Parent and Devreotes, 1999), which is achieved
through localization of PI3 kinases and the tumor suppressor PTEN
(Kolsch et al., 2008). This reorganization facilitates pseudopodia
extension (Wang et al., 2002) through actin polymerization induced
by actin-binding proteins (WASP, profilin, cofilin, capping protein)
binding to membranous PI(3,4,5)P3 and PI(4,5)P2 (Yin and Janmey,
2003) and subsequent membrane addition by vesicle transport.
Mislocalization of phosphatidylinositols disorganizes polarity of the
aforementioned actin-binding proteins (reviewed in Gassama-
Diagne and Payrastre, 2009; Nelson, 2009) and also inhibits cytoki-
nesis by a similar mechanism (Janetopoulos et al., 2005). For ex-
ample, cells lacking PTEN and PI3K are unable to create a stable
actin/myosin–based contractile ring, thus failing to form a cleavage
furrow between dividing mother and daughter cells (Janetopoulos
et al., 2005). This finding suggests that polarization of phosphati-
dylinositols at the midzone is required to initiate cytokinesis.
The exocyst may function similarly in polarity formation
Secretion from the Golgi apparatus has been suggested as the pri-
mary trafficking route for both cell polarization and cytokinesis
(Gromley et al., 2005; Nelson, 2009). However, recent evidence links
the secretory and endocytic recycling pathways, making it difficult
to dissect their individual functions. Originally, the exocyst vesicle-
tethering complex was found at the apex of the lateral membrane
domain in polarized epithelial cells (Figure 1A), where it specified
basolateral secretory-vesicle delivery (Grindstaff et al., 1998). More
recently, the exocyst was also found at the apical recycling endo-
some compartment (Oztan et al., 2007; Bryant et al., 2010) and at
the basal bodies of the primary cilium (Babbey et al., 2010; Figure
1A). In addition, the exocyst subunit Sec15 was identified as a Rab
GTPase-Rab11 effector that colocalizes at the recycling endosome
in both Drosophila and mammals (Zhang et al., 2004; Wu et al.,
2005). Thus the exocyst has distinct localizations that include the
plasma membrane, secretory vesicles, the basal body, and recycling
endosomes, which suggests not only roles in secretory vesicle fusion
at the plasma membrane and during endocytic recycling, but per-
haps various other functions.
The exocyst may be involved in regulating polarized-vectorial
membrane traffic toward the leading edge of a migrating cell during
interphase (Figure 1B) or in the opposite direction toward the mid-
body during cytokinesis (Figure 1C). A migratory cell requires de
novo plasma membrane addition at the leading edge that is driven
by membrane traffic (Lim et al., 2005). This occurs through use of the
small-GTPase RalB to confine vesicle trafficking to the leading edge,
achieving directional cell movement (Camonis and White, 2005;
Rosse et al., 2006). These vesicles then tether at the leading edge
via the RalB-recruited-exocyst complex (Rosse et al., 2006), suggest-
ing that localized membrane addition is required to create a polar-
ized migrating cell. Of interest, this same process seems to be simi-
lar, if not the same, for membrane addition at the cytokinetic bridge.
As in cell migration, RalB recruits the exocyst to the cytokinetic
bridge during abscission (Cascone et al., 2008). In addition, two in-
dependent groups showed that secretory vesicles dock via the exo-
cyst and fuse within the cytokinetic bridge (Gromley et al., 2005;
Goss and Toomre, 2008). Most important, these studies found that
vesicle fusion near the midbody ring is required for abscission. One
interesting point that these findings highlight is that vectorial mem-
brane transport toward the midbody is opposite that of membrane
transport in a migrating cell, suggesting that cytokinetic cells can
reorganize the direction of polarized membrane traffic.
During both cell migration and cytokinesis, plasma membrane
addition driven by the exocyst complex is likely coordinated with
Rab-dependent and soluble N-ethylmaleimide–sensitive fusion pro-
tein attachment protein receptor (SNARE)–dependent machinery.
One of the best examples of this possible coordination is with the
mother-centriole-localized protein centriolin. During cytokinesis
centriolin localizes to the midbody ring within the cytokinetic bridge
(Figure 2). At the bridge, centriolin can interact with both the exo-
cyst complex and a SNARE-associated protein, Snapin, which can
mediate secretory vesicle fusion (Gromley et al., 2005). In a separate
study, exocyst depletion not only caused inhibition of secretory ves-
icle fusion at the midbody, but also impaired Rab11 localization to
the cytokinetic bridge (Fielding et al., 2005). These results suggest
that the exocyst is required for both endosomal and secretory mem-
brane-trafficking steps during cytokinesis (Fielding et al., 2005;
Gromley et al., 2005), which is similar to the requirement of the exo-
cyst complex for endocytic recycling and secretory traffic to the
leading edge in polarized cells (Grindstaff et al., 1998; Zhang et al.,
2004; Wu et al., 2005; Rosse et al., 2006; Oztan et al., 2007; Nelson,
Rab GTPase family members are required for cytokinesis
Rab GTPases are key regulators of membrane traffic, with more than
60 members in mammalian cells that define particular routes within
the secretory and endocytic pathways. Rab11 is a well-established
participant in recycling endosomal trafficking. In polarized epithelial
cells Rab11 is associated with membranes in the apical portion near
the centrosome and beneath the apical plasma membrane
(Casanova et al., 1999). This localization enables Rab11 to regulate
efficient endosomal recycling to apical plasma membrane domains
(Prekeris et al., 2000). Rab11 is required for cytokinesis in Caenorhab-
ditis elegans and Drosophila and was the first Rab GTPase impli-
cated in cytokinesis in human cells (reviewed in Strickland and
Drosophila embryogenesis has provided a unique system for
studying Rab11-dependent membrane trafficking (discussed in
Strickland and Burgess, 2004). Molecular elements required for cel-
lularization of the Drosophila embryo are often homologous to
those that drive cytokinesis in mammalian cells. Of interest, Rab11
activity is essential for cellularization of the Drosophila embryo.
Dominant-negative Rab11 caused defects in membrane addition
and furrow morphology (Ullrich et al., 1996). These phenotypes
were very similar to Drosophila Nuclear Fallout mutants (Rothwell
et al., 1998), suggesting that both genes may be involved in com-
mon pathways. In fact, Nuclear Fallout is closely related to the mam-
malian Rab11-binding protein FIP3 (Hickson et al., 2003), which is
required for mammalian cytokinesis (Fielding et al., 2005; Wilson
et al., 2005).
The formation and targeting of Rab11 vesicles to membrane do-
mains within the cytokinetic bridge may be analogous to the mech-
anism for targeting Rab11 vesicles to the apical plasma membrane.
In fact, Rab11-positive recycling endosomes, together with the
Rab11 effectors FIP3 and FIP4, are required for membrane delivery
during cytokinesis and abscission, although the site of targeting is
unknown (Wilson et al., 2005). Both FIP3 and FIP4 bind the small
GTP-binding protein ARF6, which binds to the exocyst subunit
Exo70 and is required for cytokinesis (Fielding et al., 2005). One
proposed role for these complex interactions is that FIP3 and FIP4
couple Rab11-positive vesicle traffic from the recycling endosome
to the midbody, where they are tethered via interactions with ARF6
10 | H. Hehnly and S. Doxsey Molecular Biology of the Cell
We thank David Lambright (University of Massachusetts Medical
School), Charles Yeaman (University of Iowa, Iowa City, IA), Alison
Bright (Doxsey lab, University of Massachusetts Medical School),
and Benedicte Delaval (Doxsey lab, University of Massachusetts
Medical School) for critical reading of the manuscript. The National
Institutes of Health, the Ellison Medical Foundation, and the W. M.
Keck Foundation supported the work in S.D.’s laboratory. H.H. is
supported by a National Research Service Awards Postdoctoral
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polarity complex (Osmani et al., 2010).
Rab35 is a newly discovered GTPase required for cytokinesis.
Like Rab11, Rab35 localizes to the endocytic recycling pathway and
regulates cytokinesis. However, during interphase Rab35 does not
colocalize exactly with the Rab11 compartment. Rab35 functions at
an early (fast recycling) endosome, prior to the relatively slow recy-
cling endosome step regulated by Rab11 (Kouranti et al., 2006).
Whether a role exists for Rab35 in regulating either polarity in migra-
tory cells or epithelial cells is not yet known. One argument that it
may regulate polarity is that Rab35 is required during cytokinesis to
concentrate PI(4,5)P2 at the cytokinetic bridge (Figure 1C; Kouranti
et al., 2006). In addition, like Rab11, Rab35 is required during cytoki-
nesis after furrow ingression to provide polarized delivery of mem-
brane vesicles derived from recycling endosomes to the cytokinetic
bridge. This membrane could be required during abscission for na-
scent daughter cell separation (Wilson et al., 2005). Because Rab11
and Rab35 are localized to different subcellular compartments and
control distinct endocytic recycling pathways (Zerial and McBride,
2001), it is likely that there are multiple endocytic routes that are in-
dividually essential for cytokinesis and, hypothetically, polarity.
The role for Crumbs during cytokinesis
Crumbs proteins are important determinants of apical membrane
identity (McCaffrey and Macara, 2009) and may be required for cy-
tokinesis. A recent study found that the apical membrane is estab-
lished during and after cytokinesis through the delivery of Crumbs3-
positive membranes from a Rab11-regulated recycling endosome
compartment at the spindle poles that move centripetally along mi-
crotubules toward the plasma membrane (Schluter et al., 2009).
Live-cell imaging revealed Crumbs3 localization between the two
daughter cells within the cytokinetic bridge (Schluter et al., 2009).
Although these data strongly suggest that polarity is initiated during
cytokinesis, a requirement for polarity complexes in cytokinesis has
yet to be determined. Of interest, the studies of Schluter et al. (2009)
and others (reviewed in Shivas et al., 2010) have shown that the
endocytic pathway can play an important role in the localization of
polarity proteins during cytokinesis and polarity formation; there is
also evidence for a reciprocal role for polarity proteins in the regula-
tion of endocytic machinery (Balklava et al., 2007). Taken together,
these studies suggest a synergistic model in which polarity and en-
docytosis regulators may cross-regulate one another and mutually
contribute to the completion of cytokinesis and the formation and
function of polarized cells.
Establishment of polarity is important for cell migration and parti-
tioning an organism into external and internal compartments. The
discussion here suggests that polarity also functions in cell division.
This is suggested by the organization of polarity complexes to cy-
tokinetic sites and defects in cell division following loss or mutation
of polarity complex proteins (Albertson and Doe, 2003; Humbert
et al., 2006). Similarly, although the localization of polarity compo-
nents such as Crumbs and phosphatidylinositols to mitotic struc-
tures, as well as directed vesicular traffic, highlight the initial stages
of polarity during the final stages of cytokinesis, the functional rele-
vance of this reorganization is unknown. Therefore comparing com-
ponents that are involved in cytokinesis, such as Rab35, that are not
yet known to be involved in cell polarity and investigating their pos-
sible conserved function between cytokinesis and polarity may shed
light on novel molecular mechanisms. The same approach could be
used in a reciprocal manner to address whether known polarity pro-
teins not yet shown to be involved in cytokinesis have cytokinetic
We conclude that there is a likely requirement for spatiotemporal
orchestration of membrane trafficking and polarity-complex ma-
chinery to construct new polarized membranes during both cytoki-
nesis and apical surface formation. However, the precise spatiotem-
poral relationships and functional relevance of these factors have
yet to be determined. Future insights into how endocytic recycling,
secretory, and polarity pathways act together during cytokinesis will
require careful spatiotemporal analysis of these components at the
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