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Planar cell polarity signaling in neural development
Fadel Tissir and André M Goffinet
Planar cell polarity (PCP), the organization of cell sheets in the
tangential plane, is regulated by a set of ‘core’ PCP genes. Over
the last few years, evidence has accumulated that PCP
signaling is important for brain development and function. PCP
signaling in the neuroepithelium and otic placode controls
neural tube closure, the organization of inner ear sensory cells
and probably neural stem cell divisions. PCP signaling also acts
in postmitotic neurons, and regulates neuronal migration, axon
guidance as well as neuronal maturation and survival. Although
several key players in PCP signaling have been identified, their
mechanisms of action remain elusive, particularly in the
nervous system.
Address
Université Catholique de Louvain, Institute of Neuroscience,
Developmental Neurobiology, Avenue E. Mounier, 73, Box 7382, B1200
Brussels, Belgium
Corresponding author: Tissir, Fadel ([email protected])
Current Opinion in Neurobiology 2010, 20:572–577
This review comes from a themed issue on
Neuronal and glial cell biology
Edited by Michael Ehlers and Franck Polleux
Available online 14th June 2010
0959-4388/$ – see front matter
# 2010 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.conb.2010.05.006
Introduction
Planar cell polarity (PCP) refers to the organization of cell
sheets in the tangential plane, along an anatomical axis
perpendicular to the familiar, apicobasal cell polarity.
Although PCP and its regulation have been scrutinized
in Drosophila for decades [1–3], studies of PCP in
vertebrates is recent, especially in neural development
[4]. Since the nervous system derives from an epithelial
neural plate, the involvement of PCP signaling in the
neuroepithelium appears a posteriori quite trivial. What
was less predictable, however, is that PCP signaling also
plays crucial roles in axonal guidance, ependymal ciliogenesis, dendrite maturation, neural stem cell regulation,
and even neuron survival, thus making it a major player.
cells are decorated with prehairs that develop as an actinrich bundle before being incorporated in the cuticle.
Normally, hairs develop at the distal cell side and point
distally, and screenings for hair abnormalities led to
identification of ‘core’ PCP genes Frizzled, Dishevelled,
Van Gogh/strabismus, Prickle, Flamingo/starry night, and
Diego. Interestingly, the role of Frizzled in PCP was
identified before its role as Wnt receptor.
PCP signaling relies on a polarized partition of
protein complexes
The consensus view is that PCP is mediated by transient
asymmetric expression of surface membrane complexes in
different sectors of the adherens junction (AJ) belt
(Figure 1). In the wing, Flamingo is present symmetrically,
whereas Frizzled and Van Gogh are targeted to opposing
junctional domains, Frizzled to the distal side — where the
hair is located — and Van Gogh to proximal side (Figure 2).
Interactions mediated by these complexes propagate asymmetric signals from cell to cell, a distal signal via Dishevelled, and a proximal one via Prickle. A key and largely
unresolved issue is how these particular distributions are
achieved at the molecular and cellular levels [9]. Since
Flamingo is distributed both in proximal and distal membranes, it was looked at as a scaffold between adjacent cells
that stabilizes PCP protein complexes. However, recent
data showed that Flamingo mediates instructively PCP
signals by recruiting selectively Frizzled to distal, and Van
Gogh to proximal AJs [10]. AJs are located apically to
septate junctions (the equivalent of tight junctions) in flies,
whereas they are located basally to tight junctions in
vertebrates. This difference might have implications for
understanding PCP protein insertion to AJs [11]. Perhaps,
targeting to AJs in Drosophila could use mechanisms for
apical targeting, whereas it could share features of basolateral traffic in vertebrates. Another complex and controversial issue concerns the role of Wnt factors. Although they
do not mediate PCP in flies [10], non-canonical Wnt
pathways are implicated in events that resemble PCP in
zebrafish and frog, such as the convergent extension (CE)
during gastrulation [12]. In mice, Wnt factors are believed
to tune PCP signaling in the nervous system [13]. The fact
that Wnt mutants do not display PCP phenotypes might
reflect redundancy among the 19 mammalian Wnt molecules. Norrin, a non-Wnt ligand, can bind Frizzled4 (Fzd4)
[14], suggesting that unidentified Fzd ligands may be
implicated in vertebrate PCP.
Lessons from Drosophila: core PCP genes
In flies, the main readout of PCP is the organization of
hairs on the wing [2], and to a lesser extent ommadia
rotation [5], orientation of body appendages [6] and
somatosensory organ precursor division [7,8]. Pupal wing
Current Opinion in Neurobiology 2010, 20:572–577
Relationship between PCP and anatomical axes
Polarized expression of Frizzled and Van Gogh, with
symmetric expression of Flamingo, can be schematized
as elementary vectors F–V (Figure 2). One interesting
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Planar cell polarity signaling in neural development Tissir and Goffinet 573
Figure 1
Asymmetric localization of PCP protein complexes. By analogy with the
situation in the fly wing, adjacent cells (a) and (b) can interact
asymmetrically by expressing one of the three Flamingo orthologs
Celsr1, 2 or 3 (blue) in both membranes. Celsr proteins are large (more
than 3000 aminoacids) multidomain seven pass cadherins that bind by
homophilic interaction. Frizzled orthologs Fzd3 or 6 bind to Celsr in ‘cis’
in one membrane, whereas Van Gogh ortholog Vangl2 interacts also in
‘cis’ with Celsr in the apposed membrane. Fzd are seven-pass
transmembrane proteins of about 670 residues, and Vangl2 is a
tetraspanin, with very small extracellular loops, of about 520
aminoacids. Adapted from models of PCP signaling in Drosophila
(e.g. [9,10]).
issue is how are those F–V vectors oriented with respect
to anatomically defined axes? In some instances, such as
the wing, F–V vectors are parallel to the proximodistal
axis. They are also parallel to the direction of the mitotic
spindle in asymmetric cell division in sensory organs
(Figure 3) [15]. On the other hand, in the cochlea where
CE is important for elongation, F–V vectors are directed
from medial to lateral, perpendicular to the anatomical
cochlear axis. Possibly, when a structure elongates by CE
stricto sensu, via cell movement without cell division, this
may be likened to ‘a cook working his paste into a roll’,
with force applied perpendicular to the elongation movement. When a structure is modified by cell division,
however, then F–V vectors would be predicted to align
with the orientation of the spindle, parallel to the anatomical axis. If this view proves correct, the distribution of
PCP proteins should not always be consistent with the
direction of the elongating anatomical axis, further hampering interpretation.
Expression of core PCP genes during brain
development in mice
Human and mice have 10 Frizzled (Fzd1–10), four
Prickle (Prickle1–4), three Dishevelled (Dvl1–3), two
Van Gogh (Vangl1 and 2) and three Flamingo/starry night
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Figure 2
Model for PCP-mediated cell–cell interactions during neural
development. Membrane protein complexes mediate interactions
between two adjacent cells (a) and (b) or between growth cones and
guidepost cells. They provide asymmetric (polarizing) signals via
Disheveled (grey), Celsr (blue), and Fzd (green) on the one hand; and via
Prickle (orange), Celsr (blue), and Vangl2 (red) on the other hand.
Intracellular signals impact on the actin cytoskeleton, for example, via
formins, and thereby regulate development of structures such as hair or
growth cone tips. PCP signals also instruct docking of cilia and may
impact on oriented cell division as schematized in Figure 3. The
asymmetry of protein complexes specifies the direction of a PCP vector
that can be parallel or perpendicular to the anatomical axis. Adapted
from Ref. [9].
orthologs (Celsr1–3, ‘cadherin EGF laminin seven-pass
receptors 1–3’). Orthologs are also described in zebrafish
and Xenopus, sometimes under different names, and some
in duplicate because of partial tetraploidy; for example,
there are two Celsr1 (1a and 1b) in zebrafish.
PCP gene orthologs are expressed during brain development [16]. Celsr1–3 have specific expression patterns.
Celsr1 is restricted to NSC, Celsr3 predominant in postmitotic cells, and Celsr2 present in both, more in postmitotic cells than in NSC, and persists in the adult. Fzd3
and Fzd6 may be the main Frizzled orthologs implicated
in PCP. Fzd3 is widely expressed in ventricular zones of
NSC proliferation, as well as in postmitotic neurons.
Vangl2 is highly expressed at all stages, in NSC and all
neural cells, a pattern reminiscent to that of Fzd3,
whereas Vangl1 is focally expressed. Dvl1 is expressed
in NSC and postmitotic cells, and persists in the adult;
Dvl2 is restricted to NCS; and Dvl3 is confined to postmitotic cells. Prickle1 and 2 are expressed in different
regions of the developing brain, mainly by postmitotic
cells, and are not downregulated in the adult. Overall,
expression patterns suggest that PCP genes may
cooperate in two sets, both of which include Fzd3 and
Vangl2, together with either Celsr1 or Celsr2,3. Celsr1,
Fzd3 and Vangl2 would regulate PCP in NSC, whereas
Celsr2,3, Fzd3 and Vangl2 act in postmitotic neural cells.
Current Opinion in Neurobiology 2010, 20:572–577
574 Neuronal and glial cell biology
Figure 3
Tentative model for regulation of asymmetric divisions and
neurogenesis. In Drosophila, the sensory organ precursor pI divides
asymmetrically into pIIb and pIIa. The division occurs along the
rostrocaudal axis, and a PCP signal aligns the spindle along that axis, via
Van Gogh and Flamingo (rostral distribution), and Frizzled/Flamingo
(caudal distribution). A similar mechanism could apply to facial
branchiomotor (FBM) neuron migration. During facial FBM neuron
generation, a precursor would divide asymmetrically and give rise to an
ependymal (or another) cell, and a FBM neuron. Precursor division would
align along a PCP axis, under control of Celsr1 together with Fzd3 and
Vangl2. This would specify the direction taken by migrating neurons. The
ability to migrate is conferred by another PCP signal generated by
Celsr2,3 with Fzd3 and Vangl2 [33]. Adapted from Ref. [8].
PCP, the organization of inner ear receptor cells,
and neural tube closure
Actin stereocilia on the apical surface of cochlear receptor
cells form a ‘V’ centered on a primary kinocilium at the
tip. Organization of stereocilia is affected in mice with
mutations of Celsr1 [17], Vangl2 [18,19] and Fzd3 and 6
[20]. Analysis of the planar distribution of PCP molecules
suggests that a PCP signal transversal to the cochlear axis
governs the position and orientation of the kinocilium,
which in turn affects orientation of stereocilia [21]. The
organization of stereocilia in vestibular hair cells is less
evident than in the cochlea, but also controlled by PCP
signals [22]. In maculae, there is a symmetric organization
of stereocilia relatively to a line of reversal, a pattern
reminiscent of the mirror rotation of ommatidia relatively
to the equator in the fly retina. Remarkably, both patterns
are defective in PCP mutants.
Neural tube closure has been reviewed recently [23].
Mice with inactivation of Fzd3 [24], Vangl2 [25,26], and
Current Opinion in Neurobiology 2010, 20:572–577
Celsr1 [17,27] have a looping tail phenotype typical of
defective CE in the caudal neural tube. Fzd3 [24],
double Fzd3 and Fzd6 [20], Vangl2 [25,26], double
Dvl1 and Dvl2 [28] and Celsr1 [17,27] mutants have
craniorachischisis. Studies in zebrafish attributed failure
of neural tube closure to defective CE, with broadening
of the floor plate that prevents dorsal joining and closure
[29]. To our knowledge, it is not entirely clear whether
neural plate elongation proceeds by CE, or by directed
cell division, or both. Elongation by CE would predict
that F–V vectors be directed along the mediolateral
direction, whereas vectors would be aligned in the
rostrocaudal direction if mitotic divisions play a role.
Additional investigations of PCP proteins distribution
and mitotic spindle orientation are needed to understand this further. A role for Vangl2 in spindle orientation in the embryonic brain has been reported.
However, this study focused on spindle orientation
along the apicobasal axis (late in development) and
did not address orientation along the anterior–posterior
and mediolateral axes during neural tube closure [30].
Recently, craniorachischisis was reported in mice with
mutations of Sec24b, which regulates traffic of Vangl2 to
the membrane [31,32], providing a first hint at the
mechanisms whereby cells distribute Fzd, Vangl and
Celsr complexes in different regions of the cell membrane [11].
PCP, neural stem cell biology, and neuronal
migration and maturation
Expression patterns suggest roles of Celsr1 in NSC, and
Celsr2–3 in brain maturation. This ‘dual’ system was
investigated during caudal migration of facial branchiomotor (FBM) neurons from rhombomere (r)4, where they
are generated, to r6 where they settle and form nucleus
VII. Loss of function of Celsr1 in NSC results into
abnormal migration of daughter FBM neurons, in rostral,
lateral and caudal directions. This phenotype is not seen
when Celsr1 is conditionally inactivated in FBM neurons
(using Isl1-Cre mice), showing that Celsr1 function is
non-FBM neuron autonomous, and perhaps involves
oriented precursor division (Figure 3). In contrast,
mutation of Celsr2 does not compromise the direction
of migration, but shortens the caudal movement of
migrating neurons that stop prematurely and settle in
ectopic position in r4–r5 instead of r6. Double inactivation
of Celsr2 and 3 enhances this phenotype and results in
neuronal apoptosis. Mutation of Fzd3 mimics combined
inactivation of Celsr2 and 3 [33]. Inactivation of Vangl2
in mice, and of Fzd3, Celsr2 and Vangl2 in zebrafish also
perturb FBM neuron migration [34,35], confirming that
PCP signaling is involved. The view that Celsr2 and 3
regulate PCP signals required for neuronal maturation is
further supported by observations that adult Celsr2
mutant brains are atrophic, with reduced branching of
dendrites and neuronal degeneration (FT, AMG, unpublished). Studies of dendrite growth in primary cultured
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Planar cell polarity signaling in neural development Tissir and Goffinet 575
neurons indicate that Celsr2 and 3 have opposing roles
[36]. In addition to Celsr1–3, PCP signaling events probably implicate Fzd3 or Fzd6, Vangl2, and Dvl and Prickle
partners that remain to be identified. Importantly, Celsr1,
Fzd3, Vangl2, and Dvl1-2 are expressed in the adult brain
in telencephalic subependymal zones and subgranular
layer of the dentate gyrus. It will be interesting to
investigate the role of these genes in neurogenesis and
neuronal migration in the mature brain.
PCP and brain wiring
Mutations of Celsr3 and Fzd3 generate similar axonal
guidance defects along the whole neuraxis, with prominent wiring abnormalities in the spinal cord, brainstem,
mid- and forebrain [13,24,37,38], indicating that PCP
molecules have wider roles than other axonal guidance
systems which have a more local or restricted action [39].
Defective non-canonical Wnt signaling was proposed to
account for wiring defects in Fzd3 mutants [13]. On the
other hand, region-specific ablation of Celsr3 suggests
that PCP signaling is mediated by direct interactions
between growth cones and guidepost cells [38].
Whereas the role of PCP molecules in the neuroepithelium is relatively easy to conceptualize, it is more challenging to explain how PCP-like mechanisms affect
axonal pathfinding. Studies of the impact of PCP signaling on actin dynamics and/or centrosome positioning
may provide interesting cues.
PCP and ciliogenesis
PCP governs cilia development in epidermis of larval
Xenopus. Morpholino downregulation of Dishevelled1-3,
Inturned, and Fuzzy affects the actin cytoskeleton and
apical docking of ciliary basal bodies [40]. Recently,
Celsr2 and Celsr3 were shown to be required for the
development of ependymal cilia in mice [41]. Combined loss of Celsr2 and Celsr3 severely impairs ciliogenesis, leading to defective flow of cerebrospinal fluid and
lethal hydrocephalus. Although differentiation of ependymal cells is not primarily affected, ependymal cilia
never develop in normal numbers and display abnormalities in morphology, position, and planar organization.
Ciliary basal feet are misoriented, and basal bodies and
cilia assemble deep in the cytoplasm. The lateral plasma
membrane localization of Vangl2 and Frizzled3 is disrupted in ependymal cell precursors, providing strong
indication that Celsr2 and Celsr3 regulate ciliogenesis
via PCP signaling. In the inner ear, asymmetric distribution of PCP proteins is detected before and probably
required for cilia development [22,42]. Reciprocally, PCP
proteins are normally distributed in cilia-defective
mutant mice Ift888 and Kif3a [42,43], suggesting that
cilia are not essential for the proper localization of PCP
proteins. Altogether, these data show that PCP signaling
acts upstream of ciliogenesis and regulates the positioning
of basal bodies and the apical docking of cilia.
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Conclusion: towards a unifying view?
Evidence is accumulating that a main effect of PCP
signaling is to regulate actin dynamics, which is
known — from studies in brain development and other
fields — to impact on directional growth cone navigation
[44], basal body cilia docking, neuronal migration [45],
dendrite growth and maintenance [46], and on directed
mitotic division, at least in oocytes [47]. Key questions
remain. We do not know whether extracellular signals are
involved in PCP signaling, nor the links between PCP
proteins and the actin microfilament network. About the
latter, formin proteins Daam1 and Daam2 interact physically with the Dvl adapter and mediate interactions
between actin microfilaments and microtubules, making
the formin family an obvious candidate [48].
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