REVIEW
review
Organogenesis 7:3, 1-15; July/August/September 2011; © 2011 Landes Bioscience
Planar cell polarity in Drosophila
Saw Myat Thanda W. Maung and Andreas Jenny*
This manuscript has been published online, prior to printing. Once the issue is complete and page numbers have been assigned, the citation will change accordingly.
Department of Developmental and Molecular Biology; Department of Genetics; Albert Einstein College of Medicine; New York, NY USA
Key words: planar cell polarity, Drosophila, non-canonical Wnt signaling, fat, dachsous, fizzled, protein asymmetry, eye, wing,
abdomen
Abbreviations: APF, after puparium formation; Aos, Argos; A/P, antero-posterior; Atro, Atrophin; CRD, cysteine rich domain;
Dgo, Diego; Dl, Delta; Drok, Rho kinase; Ds, Dachsous; Dsh, Dishevelled; D/V, dorso-ventral; EGFR, epidermal growth factor
receptor; FH (2/3), Formin homology domain (2/3); Fj, Four-jointed; Fmi, Flamingo (a.k.a. Stan, Starry-night); Ft, Fat;
FRAP, fluorescence recovery after photobleaching; Frtz, Fritz; Fy, Fuzzy; Fz, Frizzled; GBD, Rho family GTPase binding domain;
In, Inturned; JNK, Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; Msn, Misshapen; Mwh, Multiple wing hairs;
N, Notch; Nmo, Nemo; PCP, planar cell polarity; Pk, Prickle; PR, photoreceptor; SOP, sensory organ precursor;
Stbm, Strabismus (a.k.a. Vang, van‑gogh); Wg, Wingless
In all multicellular organisms, epithelial cells are not only
polarized along the apical-basal axis, but also within the
epithelial plane, giving cells a sense of direction. Planar cell
polarity (PCP) signaling regulates establishment of polarity
within the plane of an epithelium. The outcomes of PCP
signaling are diverse and include the determination of cell
fates, the generation of asymmetric but highly aligned
structures, such as the stereocilia in the human inner ear or the
hairs on a fly wing, or the directional migration of cells during
convergence and extension during vertebrate gastrulation.
In humans, aberrant PCP signaling can result in severe
developmental defects, such as open neural tubes (spina
bifida), and can cause cystic kidneys. In this review, we discuss
the basic mechanism and more recent findings of PCP signaling
focusing on Drosophila melanogaster, the model organism in
which most key PCP components were initially identified.
the abdomen. More complex examples of PCP in flies are the
alignment of sensory bristles, which depend upon the proper orientation of asymmetric cell divisions and the exquisite arrangement of the facets (ommatidia) of the compound eye, in which
cell fate specification and coordinated rotation of cell clusters are
key to appropriate polarity. Fundamental to the control of these
processes is the non-canonical Wnt/Frizzled (Fz)-PCP signaling
pathway (note that during Drosophila gastrulation a different
mechanism is used for planar polarization that is discussed in
refs. 3 and 4 and will not be discussed in this review).
In vertebrates, non-canonical Wnt signaling regulates several
critical developmental processes. Convergence and extension during gastrulation and the formation of tubular organs such as the
kidney, heart, lung and female reproductive tract require polarized migration and cell intercalation.5-10 For instance, aberrant
polarization of mesodermal cells due to lack of Fz-PCP signaling
prevents the narrowing (convergence) and elongation (extension)
of the body axis. In humans, loss of PCP thus causes neural tube
closure defects in 1 out of every 1,000 live births11,12 due to the
failure of the neural folds to merge at the midline. Additionally,
aberrant non-canonical Wnt signaling contributes to other disorders such as ciliopathies (including certain renal diseases) 13,14 and
deafness, the latter due to misorientation of the ciliary bundles
or the hair cells of the vertebrate inner ear.15-18 PCP proteins also
contribute to defense mechanisms such as wound healing where
mammalian/vertebrate PCP homologs and downstream effectors
in conjunction with the bHLH transcription factor Grainyhead
are required.19
A common feature of Fz-PCP signaling underlying these
diverse functions is modulation of the cytoskeleton, whether for
orientated cell division or cell movement and migration, and thus
cytoskeletal regulators are key effectors of the upstream PCP signaling modules.
Taking into account the large array of developmental and
pathological mechanisms that require PCP, research in this
field is both prolific and diverse. Historically research into PCP
expanded after it was first demonstrated in flies, as Drosophila is
an excellent genetic model system.20,21 We will give an overview
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Introduction
Establishment of polarity is a major developmental process in
multicellular organisms. Cell polarity permits cells to organize
and maintain tissues and more elaborate structures and organs.
Cell polarity relies on the establishment of the x-, y- and z-axes.
Two basic types of polarity exist: apical basal polarity separates
the cell membrane into an upper and lower compartment separated by tight and adherens junctions and thus establishes the
z-axis, which allows a separation of lumina from basement membranes.1,2 Cellular organization within the x-y plane is referred to
as epithelial planar cell polarity or tissue polarity (PCP). In its
most basic form, PCP is manifest as cellular asymmetries across
the epithelial layer and thus confers directional information. In
Drosophila, PCP is seen in its simplest form in the alignment
of actin hairs (trichomes) on the wing and abdomen (Fig. 1),
which all point toward the distal wing margin or posteriorly on
*Correspondence to: Andreas Jenny; Email: [email protected]
Submitted: 07/26/11; Revised: 09/14/11; Accepted: 09/18/11
DOI:
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Figure 1. PCP phenotypes in Drosophila. (A and B) Enlarged view of part of an adult wild-type (A) and stbm mutant (B) wing. Note the irregular wing
hair swirls of the stbm mutant. Distal is to the left, anterior is up. (C) Trichomes on the cuticle of abdominal tergites. Note the posterior non-autonomy
of fz mutant clones (outlined by red lines), where trichomes point anteriorly toward the clone (red arrows) instead of posteriorly. Image courtesy of P.
Lawrence (adapted with permission).72 (D and E) Examples of wild-type (D) and fz mutant (E) adult eye sections showing the semi-crystalline arrangement of ommatidia. The schemes below the sections indicate the polarity of ommatidia, with arrows drawn from R3 to R1 with the flag pointing toward R4. Note the randomized chirality and degree of rotation in the fz mutant. Yellow dots represent the equator. The insert in (D) is a high magnification of a single ommatidium with the photoreceptors numbered (R8 is below R7 and thus cannot be seen). (E and F) Scanning electron micrographs of
the dorsal thorax of adult flies. (E) Wild-type: thoracic bristles are well aligned and point toward the posterior. However, in a fz mutant (F), bristles are
misaligned due to the random planar division axis of SOP cells. Images courtesy of P. Adler (adapted with permission).65
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over current knowledge of the mechanism of PCP establishment
in different Drosophila tissues and refer to the accompanying
reviews for more details about the relevant processes in vertebrates.
Establishment of PCP in the Wing
The adult Drosophila wing is one of the simplest and best characterized model systems for studying planar cell polarity. Each
wing cell produces a single actin rich protrusion called a trichome
or hair (Fig. 1A; reviewed in ref. 22). Every trichome is polarized
along the proximal/distal axis with the posterior trichomes close
to the wing margin deflected toward it. The wing develops from
a flat, single layered epithelium called the wing imaginal disc
in the larva. In addition to the wing and wing hinge, the wing
imaginal disc also gives rise to parts of the body wall and adult
thorax. In the early pupal stages, the wing imaginal disc undergoes a series of morphological changes called evagination, eversion and elongation, during which the wing blade pushes out of
the imaginal disc. These processes are dependent upon mechanical forces and cell rearrangements as the tissue organizes itself
into the structures of the adult thorax and wing.23 Later in pupal
development (around 32 hours after puparium formation [APF]),
polarized wing hairs develop under the control of the core PCP
2
genes (Table 1). By this stage of development, cell division and
differentiation are largely complete,24-26 making the wing a nice
system to study planar polarity.
Wing hair formation begins with the localization of actin
and microtubule rich pimples on the distal apical surface of the
wing imaginal disc cells (Fig. 2A).27 The actin and microtubules
within these pimples polymerize to form microvilli and eventually the “prehair,” which sprouts out at the distal vertex of each
cell.28-31 The subcellular location of prehair initiation is highly
correlated with cell polarity and polarity mutations manifest in
changes in the number and location of prehair emergence.31 In
PCP mutants, as described in more detail below, single or multiple trichomes tend to arise ectopically in the cell center and the
trichomes are not properly aligned with the overall wing axis.22
PCP in the Sensory Organ Precursor and Abdomen
PCP can also be observed on the adult Drosophila thoracic cuticle,
which is covered with distally pointing, stereotypically positioned
mechanosensory bristles (macro- and micro-chaetae; Fig. 1F).
The thoracic bristles differ from wing blade hair cells in that they
are innervated and their planar polarity is dependent upon the
asymmetric division of a sense organ precursor (SOP) cell. The
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Table 1. Summary of PCP genes and their vertebrate paralogs
Tissues
affected in
Drosophila
(Potential)
Vertebrate
paralogs
Molecular features
Fly references
Vertebrate
references
frizzled (fz)
E, W, S, A
Fz3, 6
and 7
seven-pass transmembrane receptor, binds Wnt
ligands, Dsh; recruits Dsh and Dgo to membrane
21, 35, 36, 40, 65, 71, 78, 85,
86, 94, 96, 112, 129, 155–160
17, 77, 80,
100, 161–165
dishevelled (dsh)
all adult tissues
Dvl1–3,
xDsh
cytoplasmic protein containing DIX, PDZ, DEP
domains, recruited to membrane by Fz, binds Fz,
Pk, Stbm and Dgo
36, 66, 81, 83, 84, 86, 112,
113, 166–171
16, 172–179
flamingo (fmi)/
starry night
(stan)
all adult tissues
Celsr 1–3
cadherin with seven-pass transmembrane receptor features, homophillic cell adhesions
49, 58, 61, 68, 91, 95, 98, 180
181–184
diego (dgo)
E, W, T in GOF*
Inversin,
Diversin
cytoplasmic Ankyrin repeat protein, recruited
to membrane by Fz, binds Dsh, Stbm and Dgo.
Diversin/Inversin in vertebrates
62, 85, 86, 93
16, 185–191
strabismus
(stbm)/van-gogh
(Vang)
all adult tissues
Vangl1, 2
4-pass transmembrane protein, binds Pk, Dsh
and Dgo, recruits Pk to membrane
34, 67, 70, 92, 192, 193
7, 8, 100,
194–212
prickle (pk)
all adult tissues
Pk1, 2
cytoplasmic protein with 3 LIM domains and PET
domain, recruited to membrane by Stbm, physically interacts with Dsh, Stbm and Dgo
64, 86, 87, 89, 93, 213
87, 99, 101,
214–217
PCP gene
Core genes:
Ft/Ds module:
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all adult tissues
Fat4
atypical cadherin, binds Ds and Atrophin
49, 51, 53, 72, 107, 110, 147,
148, 150, 151, 154, 218–220
221
ds
all adult tissues
Dchs1
atypical cadherin, binds Ft
49, 51, 107, 141, 147, 148, 151,
218, 220
145
fj
all adult tissues
mFjx
Type II transmembrane protein, golgi resident
luminal kinase
54, 60, 143, 144, 146, 147, 153
145
RhoA/Rac
E, W*
Rho, XRac1
small GTPase, acts downstream of Dsh
29, 114, 115, 135, 222, 223
224, 225
rho kinase (drok)
E, W*
Rock1, 2
Ser/Thr kinase
115, 116, 135
226
DAAM1
Formin, actin polymerizing, binds Dsh, RhoA
134
227, 228
Ste20 like Ser/Thr kinase
119, 229, 230
AP1 transcription factor component
117
Secondary
genes:
daam
misshapen (msn)
E, W, T*
jun
E
(JNK)
fos (kayak)
E
AP1 transcription factor component
114, 117–119
Notch (N)
E
transmembrane protein
78, 91, 97, 120–122, 232–235
Delta (Dl)
E
transmembrane protein
nemo (nmo)
E
Ser/Thr kinase distantly related to MAPKs, binds
Stbm, b-catenin, phosphorylates b-catenin
123, 124, 236
argos (aos)
E
EGF (Spitz) binding inhibitor
126, 127, 237–240
mushroom body
defective (mud)
T, S, A
Coiled coil microtubule binding protein interacts
with Pins-Gαi complex to regulate spindle orientation during asymmetric cell division
36
partner of inscuteble (pins)
T, S, A
GoLoco domains, Tetratricopeptide (TPR) repeat
motif, binds G-proteins, Inscuteable and Mud to
orient mitotic spindle during asymmetric division
34, 241
NuMa
231
36
Vertebrate genes indicated in cases where a PCP related function has been described. Tissue affected in Drosophila: A, abdomen; E, eye; S, SOP cells;
T, thorax; W, wing. *other tissues not tested. See text for details.
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Table 1. Summary of PCP genes and their vertebrate paralogs (continued)
G protein binding-formin homology 3 (GBDFH3) protein, regulates site of hair initiation and
inhibits ectopic secondary hair formation, acts
downstream of In/Fy/Frtz
31, 129, 130, 133
xFy, mFuz
Putative four-pass transmembrane protein, localization of Mwh
129, 157, 242
243–245
W
xInt, mIntu
Putative two-pass transmembrane, PDZ domain
protein, binds and localizes Mwh
129, 132, 157, 246, 247
243, 248
W
xFrtz
Coiled coil WD40-repeat cytoplasmic protein,
localization and phosphorylation of Mwh
129, 132, 249
250
multiple wing
hairs (mwh)
W
fuzzy (fy)
W
inturned (in)
fritz (frtz)
Vertebrate genes indicated in cases where a PCP related function has been described. Tissue affected in Drosophila: A, abdomen; E, eye; S, SOP cells;
T, thorax; W, wing. *other tissues not tested. See text for details.
SOP undergoes three rounds of polarized asymmetric division to
produce the neuron, sheath cell, socket cell and shaft cell of the
bristle (Fig. 2B; reviewed in ref. 32 and 33). The correct identity
of the SOP daughter cells, pIIb and pIIa, is determined by asymmetric Notch signaling due to anterior distribution of Numb in
the SOP (Fig. 2B). Expression of Bazooka at the posterior cortex limits Numb to the anterior cortex of the SOP. Numb is a
Notch inhibitor and is differentially inherited by the anterior pIIb
daughter cell upon SOP division. Numb in the pIIb cell biases
the direction of the Notch signal to its sister pIIa cell, which then
adopts a non-neural fate. The SOP spindle is aligned with the A/P
body axis and its orientation and the identity of daughter cells are
dependent upon the asymmetrical distribution of Bazooka/Par6/
aPKC at the posterior pole and Discs large/Partner of Inscuteable/
G-protein α-subunit (Dlg/ Pins/GαI) at the anterior pole of the
mitotic SOP (Fig. 2B).32,33 PCP genes are required for the asymmetric polar distribution of the Bazooka and Pins complexes34,35
and for spindle alignment through the microtubule and dynein
motor binding protein Mushroom body defective (Mud).36
In PCP mutants, mitotic spindle orientation is randomized
with respect to the A/P34,35 similar to mud mutants. Mud links
the posteriorly localized core PCP component Dishevelled (see
below) to microtubules and Dynein thereby physically attaching and orienting the spindle with the A/P axis (note that Mud
also anchors the Pins complex to the spindle on the anterior side,
ensuring the appropriate slightly anterior basal tilt of the spindle
axis).36 Thus, in the SOP, PCP ensures the proper asymmetric
distribution of the cell fate determinants by controlling the alignment of the axis of division with the global A/P axis of the tissue.
Recently it has been shown that intertissue mechanical stress
can affect the position and orientation of thoracic bristles so
much so that there appears to be a defect in planar cell polarity. The chascon mutation is such an example where the tendon
cells that attach the fly cuticle to the underlying musculature are
shortened, causing puckering and misorientation of the overlying
epidermal cells. However, chascon has no effect on the expression
or distribution of core PCP proteins and its PCP-like defect is
rather indirect.37
The abdominal cuticle consists of three distinct regions originating from bilateral pairs of histoblast nests in each segment:
the dorsal pigmented epidermis called the tergite and two ventral
regions called the pleura and sternite.38 The role of PCP signaling
in the abdomen is best studied in the epidermis of the tergite. It
consists of both sensory bristles and smaller non-innervated hair
cells called trichomes (Fig. 1C) that are polarized along the A/P
axis upon PCP signaling.
PCP in the Compound Eye
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4
The Drosophila eye is one of the most magnificently ordered
structures and develops from the larval eye imaginal disc. The
eye is made up of around 800 ommatidial units, each containing
eight photoreceptor cells as well as 12 other support cells. The
six outer photoreceptors within each ommatidium (R1–R6) are
organized in a trapezoid shape with the two inner photoreceptors
(R7 and R8) arranged on top of each other in the center of the
trapezoid (Fig. 1D). The eye disc is bisected by an equator (the
D/V midline) and the ommatidia of the dorsal and ventral hemispheres form mirror images. Thus cells of the ommatidial units
are precisely organized with respect to neighboring ommatidia
as well as the anterior-posterior and dorsal-ventral eye margins.
In PCP mutants, the ommatidia are generally formed properly
but their orientation with respect to the D/V and A/P axes are
randomized (Fig. 1E; reviewed in ref. 39 and 40).
The presumptive eye field is specified by the homeodomain
protein Eyeless and its associated regulatory network (reviewed in
ref. 41). Prior to eye differentiation Wingless (Wg) is expressed at
the dorsal and ventral margins of the eye disc and forms an activity
gradient, with the highest activity at the dorsal and ventral poles
and the lowest at the equator. Canonical, β-Catenin-dependent
Wg signaling then specifies dorsal cell fates through homeobox
genes of the iroquois complex. This ultimately leads to activation
of Notch at the midline thereby defining the equator.42,43
Eye differentiation starts with the initiation of the morphogenetic furrow (MF) at the posterior end of the equator.
The MF then moves progressively toward the anterior leaving differentiating photoreceptors and support cells in its wake
(Fig. 2C). The first photoreceptor specified is the founding R8
of each ommatidium via lateral inhibition mediated by Notch
signaling.44-47 This is followed by EFGR-dependent pair wise
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Figure 2. Schematic of PCP in the fly. (A) Proximal-distal orientation of hairs in a group of adult wing cells. (B) Asymmetric division and spindle orientation of SOP’s is determined by anterior localization of Pins and Numb and posterior localization of the Baz/Par3 complex to produce N signaling asymmetries and antero-posterior alignment of the adult bristle. (C) Schematic of a developing third instar eye imaginal disc with the dorso-ventral midline
(equator) in gray and the morphogenetic furrow (MF) in brown. The R3/4 pair is initially equivalent (pale yellow). The cell of the R3/4 pair closer to the
equator is specified as R3 (yellow) upon Fz-PCP signaling, while its neighbor becomes R4 (red). Ommatidia rotate 90° in opposing directions on either
half of the eye.
recruitment of R2/R5 and R3/R4 (reviewed in ref. 48). The
immature five-cell precluster initially organizes into an arch
shape with R3 and R4 in perpendicular alignment to the equator (Fig. 2C). As the remaining photoreceptors R1/6 and R7 are
recruited, the photoreceptors form a tight cluster and rotate 90°
clockwise in the dorsal hemisphere and 90° anticlockwise in the
ventral hemisphere until the R3 of each unit becomes the most
polar with respect to each side of the equator, thus forming a mirror image about the equator (reviewed in ref. 39 and 40).
PCP signaling specifies the R3 vs. the R4 cell fate. The R3/
R4 precursors are initially equivalent and aligned perpendicular
to the equator (Fig. 2C). Before rotation begins, PCP signaling
specifies the cell closest to the equator as the R3 and the abutting
polar cell as the R4. PCP mutants show a randomization of the
R3/4 cell fates and a randomization of the direction and extent
of their rotation (Fig. 1E).
The Core PCP Module
Over the last two decades, it has become clear that there are
two major systems contributing to PCP signaling, the Fat/
Dachsous system (Ft/Ds) and the core PCP system (a.k.a. Fz/
Fmi system). The relationship between the two, however,
remains unclear. The Fat/Dachsous system is mainly composed
of two atypical cadherins Ft and Ds and the golgi resident kinase
Four-jointed (Fj) 49-54 and possibly has long range effects on PCP
(see below). On the other hand, central to the core PCP are the
“core PCP proteins,” which are components of the non-canonical
Wnt/PCP pathway and are generally required for the establishment of PCP in all tissues. Non-canonical Wnt signaling differs
significantly from canonical, β-Catenin-dependent Wnt signaling. During canonical Wnt β-Catenin signaling, a Wnt ligand
binds a Frizzled (Fz)/Lrp receptor complex leading to Dishevelled
(Dsh) activation and ultimately inhibition of the β-Catenin
destruction complex. Stabilized β-Catenin can then enter the
nucleus to regulate transcription. Arguably the most important
function of canonical Wnt signaling is the control of embryonic
segmentation in flies and the specification of the dorsoventral
axis of the vertebrate body plan (reviewed in ref. 55).
Non-canonical Wnt signaling is independent of β-Catenin,
but does rely upon the seven pass transmembrane receptor Fz
and the adaptor protein Dsh. In contrast to vertebrates, where
it has been shown that Wnt ligands form an integral part of the
core PCP pathway and could have either permissive56 or instructive57 roles, loss of all Wnts expressed in Drosophila wing cells
at the time of PCP signaling does not cause PCP phenotypes58
(note though that overexpression of dWnt4 can cause some PCP
defects, for more detailed review ref. 39, 59 and 60). Additional
PCP-specific core components are the tetraspanin Strabismus
(Stbm, a.k.a. Van-Gogh [Vang]), the seven-pass transmembrane
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of lower inferred fz activity, but were not reported for stbm.71
The reason for the absence of non-autonomous effects of stbm
mutants in the eye is unknown, but it could simply be due to
tissue-specific mechanistic differences or the effect may be too
weak to propagate across non-photoreceptor cells in the developing eye disc and thus would not be identifiable in adult eye
sections. Interestingly though, non-autonomous PCP effects
are not unique to the fly, but have also been reported for the
mouse, Xenopus and zebrafish and thus appear to be a general
characteristic of the mechanism of PCP establishment.76-80
Downstream of Fz, the signal is transduced to Dsh, the central PCP adaptor protein consisting of three protein-protein
interaction domains (a DIX, PDZ and DEP domain; reviewed
in ref. 81). Dsh acts as a hub for various protein interactions
and its “activity” appears to be modulated by the Abl kinase.82
Apical membrane recruitment of Dsh by Fz involves direct
contacts between the PDZ and DEP domains of Dsh and the
third intracellular loop and the C-terminal domain of Fz.83-85
Furthermore, Dgo and Pk can both bind to the N-terminally
extended PDZ region of Dsh with Pk also binding to the DEP
domain.86,87 Loss of the “intracellular” PCP factors Dsh, Dgo
or Pk lead to strictly cell autonomous defects in the eye, wing
and (where tested) abdomen.62,72,74,88,89
Genetic interaction experiments, clonal analyses in the eye
and overexpression experiments in the wing in addition to
various protein interaction assays led to a model in which Dsh
and Dgo act positively on Fz-PCP signaling, while Stbm and
Pk have antagonistic effects (reviewed in ref. 39, 40 and 90).
As discussed above, R3/4 cell fate specification is essential for
correct orientation of the ommatidia in the eye. Clonal analysis
at single cell resolution demonstrated that fz and dgo are required
in R3, while stbm and pk are required in R4.70,71,86,89 Interestingly,
R3/4 mosaics with fz-/- R3 precursors (and a wild-type R4 precursor) or stbm mosaics with a mutant R4 precursor (but a wildtype R3 precursor) adopt the wrong chirality in more than 95%
of all cases, demonstrating that Fz and Stbm are instructive and
suggest direct communication between R3 and R4 at some stage
during eye development.70,71
Flamingo is an additional core PCP gene conserved among
all species studied. Fmi is able to undergo homotypic interactions across cell membranes.68 In the eye, fmi is required in the
R3 and R4 cells, initially to allow proper fz function and later
to repress it.91 In contrast to fz and stbm, fmi acts cell autonomously in all tissues,61,68,72,91 but is required to propagate the nonautonomous effects of fz.72 Furthermore, Fmi, Fz and Stbm are
mutually required for each other’s proper apical localization or
maintenance.92-95 Fmi can be co-immunoprecipitated with Fz58
and, at least in mice, with Stbm.77 In addition, the extracellular
cysteine rich region of Fz (CRD) interacts with Stbm96 suggesting the existence of a protein complex including Fz, Stbm and
Fmi at apical junctions (Fig. 3; see also next section).
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Figure 3. Model representing asymmetric protein-protein interactions
across distal-proximal cell and polar-equatorial cell-cell contacts. See text
for details.
atypical cadherin Flamingo (Fmi, a.k.a. Starry-night [Stan]) and
the cytoplasmic proteins Prickle (Pk; a.k.a. Prickle-spiny-legs)
and Diego (Dgo).61-71 With the exception of Dgo, which has no
loss of function phenotype in SOP divisions on the thorax, all of
these proteins including their vertebrate paralogs are required for
proper tissue polarity in all tissues studied.
In Drosophila, loss of core PCP genes lead to typical PCP
defects, such as wings with aberrant hair polarity (Fig. 1) and hairs
emanating from the center of the pupal wing cells rather than at
the usual distal end of the cell.21,61 Similarly, lack of these genes in
the eye cause chirality inversions and ommatidial rotation defects
(Fig. 1E; reviewed in ref. 64, 68, 70 and 71). Interestingly, fz
and stbm mutants, but not fmi, dgo, pk or dsh mutants, also cause
non-autonomous PCP defects on the wing and abdomen: mutant
clones (patches of mutant cells within a wild-type background)
affect the polarity of their genetically wild-type neighbors.21,67,72
fz mutant clones show a directed non-autonomy affecting the
polarity of distal or posterior wild-type cells on the wing and
abdomen (Fig. 1C), respectively, while stbm/vang mutant clones
show a proximal/anterior non-autonomy. These data initially led
to a model whereby PCP in the wing hairs point along a gradient
of fz activity due to either a diffusible signal or a relay mechanism.73 However, local propagation of PCP defects across clonal
borders without the inference of a diffusible factor is also consistent with certain mathematical models based on feedback loops
between the different PCP proteins74,75 (Fig. 3; see also below).
In the eye, non-autonomous effects of core PCP mutants have
only been noticed on the polar side of fz clones, again the side
6
Asymmetric Protein Localization
Transient asymmetric localization of core PCP proteins across
adjacent cell membranes was first observed in flies and is most
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probably conserved in analogous situations in vertebrates. Fz, Dsh and Dgo
are recruited to the apical junctions
at the distal side of wing cells prior to
the time of prehair initiation, while
Stbm and Pk localize to the proximal
side of a cell (Fig. 4A).83,93,94,97 Fmi is
also enriched along the proximo-distal
junctions, but localizes to both sides,
consistent with its ability to form
homotypic interactions.68,95 Although
it has not been demonstrated that this
asymmetry is functionally required,
it is intriguing that Dgo and Fz transiently localize to the polar side of R3
at the R3/4 cell border of the eye, while
Stbm is enriched at the equatorial side
of R4 93,94,97 (Fig. 4B). Similarly, Fz and
Stbm are localized to opposite ends in
the SOP cells (Fig. 4C),34,35 while Fmi
is uniformly distributed.98 Asymmetric
core PCP protein localization has also
been observed in vertebrates. Fz6, Dvl2
Figure 4. Asymmetric localization of core PCP proteins. (A) Fz (pink) and Stbm (blue) are transiently
(one of the Dsh paralogs), Vangl2 (a
asymmetrically localized in wing cells with Fz localizing to the distal apical membrane and Stbm loparalog of Stbm) were found to localcalizing proximally. (B) In the five-cell precluster of the eye imaginal disc, expression of Fz and Stbm
ize to opposite sides in sensory hair cells
are initially equivalent in the presumptive R3/R4 cells but as development continues, the ommaof the mammalian cochlea or vestibular
tidium starts to rotate and Fz becomes localized to the R3 side of the R3/R4 membrane border while
system.16,17,80,99,100 Furthermore, ectopiStbm localizes to the R4 cell membrane. (C) In the SOP of the bristle Fz localizes to the posterior
membrane and Stbm localizes to the anterior membrane before asymmetric division. Where tested,
cally expressed Pk and Dsh localize anteDsh and Dgo colocalize with Fz, while Pk colocalizes with Stbm (for details see text).
riorly and posteriorly, respectively, in
intercalating mesenchymal cells during
convergence and extension during zebrafish gastrulation.76,101-1033 than more diffusely localized (e.g., lateral) Fz/Fmi, which is readHow asymmetric localization of core PCP proteins is achieved ily endocytosed. This nicely supports earlier data demonstrating
is a key question in understanding the mechanism of PCP. Several preferential distalward movement of Fz “particles” comprised of
possibilities can be envisioned such as directional transport of Fz, Fmi and Dsh along polarized non-centrosomal microtubules
newly synthesized proteins, selective endocytosis, recycling to in wing cells prior to wing hair initiation.106 Interestingly, P/D
other sites in the cell or differential protein stability. Indeed, polarization of the microtubule cytoskeleton is independent of
evidence for most of these processes comes from studies in the Fz, but rather due to an excess of faster growing, distally localDrosophila wing. Fmi is localized asymmetrically in a radial dis- ized microtubule plus ends (at least in certain areas of the wing
tribution around the D/V boundary of the 3rd instar wing imagi- blade) that are under the control of the Ft/Ds system.107 Finally,
nal disc (corresponding to the future wing margin) before PCP evidence for differential protein stability contributing to asymsignaling is thought to occur.104 Recently, it has also been shown metric PCP protein localization comes from studies in mammathat stable Fz containing protein complexes are initially radially lian cell culture, where it was shown that a Dsh/Par6 complex
asymmetric [i.e., perpendicular to the developing wing margin can recruit SMURF ubiquitin E3 ligases to target Pk for degradaat early pupal stages (around 15 h APF)].26 Careful quantifica- tion.108 The mechanism underlying PCP protein asymmetry has
tion of live video imaging of pupal wing development demon- not been addressed in other tissues.
strated that these stable Fz foci became realigned perpendicular
to the proximal-distal axis over time (i.e., the “well-known” P/D
How can Non-cell Autonomous PCP Phenotypes be
enrichment described above) due to the cells “flowing” and conExplained?
comitantly rotating to their final position upon wing hinge contraction and wing blade expansion caused by anisotropic tension Initial mutant analyses and overexpression experiments led to a
(review in ref. 26 for a theoretical description of the process). model whereby wing hairs orient along a fz activity gradient from
The existence of stable PCP (Fmi) foci was confirmed recently a higher toward lower Fz activity.109 Similarly, trichomes on the
in FRAP experiments and by quantifying the endocytic removal abdomen and the ommatidia of the eye orient along an A/P and
of Fmi and Fz from the membrane over time.105 Interestingly, equatorial/polar Fz activity gradients.71,72,110 However, the situaPCP protein foci are more stable and less subject to endocytosis tion appears to be more complicated. Based on genetic data from
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www.landesbioscience.comOrganogenesis
7
the wing and protein interaction assays, feedback models have
been proposed in which distal Fz/Dsh complexes inhibit proximal Stbm/Pk complexes in cis and stimulate them in trans (across
the cell boundary; Fig. 3). Analogously, proximal Stbm/Pk complexes would stabilize Fz/Dsh complexes in trans while inhibiting
them in cis (Fig. 3).87 Furthermore, Dgo, as a part of a Fz/Dsh
complex at the distal membrane can compete with Pk for Dsh
binding and it is thus plausible that such a competition mechanism alters the stability of higher order protein complexes.86
Mathematical modeling predicts that such a feedback mechanism
is sufficient to explain the observed local non-autonomous effects
in the wing (once an initial global polarity has been set up).74
However, in vivo, the observed non-autonomous effects of Fz
and Stbm can be temporally separated from their requirement
in autonomous core PCP function and precede the formation
of visible protein asymmetries (6–24 h APF vs. 24–35 hrs APF;
reviewed in ref. 8, 52, 96 and 111). Even though fmi on its own
unexpectedly does not cause non-autonomous defects, Fmi, Stbm
and Fz mutually depend on each other for their proper localization or stabilization close to the apical cell junctions in the
wing and eye.58,92,94,112 Furthermore, propagation of fz and stbm
non-autonomy requires fmi.49,72 Fmi could thus simply stabilize
Stbm and Fz at the apical junctions or more directly affect their
“activity.” Based on experiments in the abdomen, Fmi has been
proposed to activate Stbm across the membrane, a function that
is inhibited by Fz.72 According to this model, Stbm would inhibit
Fz activity autonomously, which, in combination with a gradient
of “factor X” that limits fz activity across the tissue, is sufficient
to explain the observed non-autonomous phenotypes.72 As mentioned above, Fmi, Fz and Stbm can interact with one another,
thus Fmi could directly promote an inhibition of Stbm by Fz
rather than actively signal.96 Alternatively, asymmetrically acting
homodimers of Fmi comprised of two functionally distinct forms
(e.g., differentially modified forms) have been proposed to mediate different responses in adjacent cells to generate molecular
asymmetries.58 Intriguingly, different domain requirements have
been reported for P/D targeting of Fmi: a version of Fmi lacking
the intracellular C-tail preferentially localizes to the distal side
of wing cells, suggesting that Fmi populations may indeed be
distinct (or at least that distinct regions mediate interactions with
other core PCP proteins).95 Furthermore, demonstration that the
extracellular CRD of Fz can bind to Stbm expressed on the surface of cells in culture together with the requirement for Stbm
and Fz to propagate each others non-autonomous effects suggests
a model in which Stbm serves as a ligand for Fz for the early
non-autonomous phase of PCP signaling.96 This is consistent
with the observation that fz, stbm double mutant clones in wings
only show the same distal non-autonomy as fz single mutant
clones.96 For all these models it remains intriguing though that
Fmi mutant clones show no non-autonomous behavior.
properly, while on the wing and abdomen trichome growth has
to be initiated properly. These tissue-specific requirements rely on
genes that are often called secondary PCP genes. It is important
to note that several of these genes also have more general functions in the regulation of the cytoskeleton and are thus not truly
PCP-specific.
PCP Effectors in the Eye
Mostly based on genetic interaction studies and some loss of
function analysis, Rho family GTPases such as RhoA and Rac
have been placed downstream of Dsh in eye.113-115 Similarly, Rho
kinase (Drok) affects ommatidial rotation (and wing hair development; reviewed in ref. 116).
In addition, based on genetic evidence, the Ste20-like kinase
Misshapen (Msn) and components of a JNK type MAPKinase
cascade, Hemipterous (Hep), a JNKK and Basket (Bsk), a JNK,
and the transcription factors Jun and Fos were placed downstream of Rho and Rac to specify R3/4 fate and control ommatidial rotation.113,114,117-119 Ultimately, transcriptional regulation
includes the upregulation of Delta (Dl), a ligand of the Notch
(N) receptor in the R3 precursor. Delta then signals to Notch
in R4 to promote R4 cell fate. Thus, PCP signaling ensures the
direction of a Delta/Notch-mediated mutually exclusive cell fate
decision.120-122 The involvement of Rho family GTPases and JNK
signaling during PCP signaling in the eye remains controversial,
as mutational analysis shows only weak phenotypes possibly due
to redundancies (reviewed in ref. 89).
Furthermore, in addition to Rho kinase and its substrate
Myosin II and several cell adhesion components (reviewed in
ref. 39), the MAPK related kinase Nemo (Nmo),123,124 and
the EGF signaling inhibitor Argos (Aos),125-127 are specifically
required to coordinate ommatidial rotation. In particular, Nemo
interacts genetically and physically with core PCP components
(Pk and Stbm, respectively) and also phosphorylates β-Catenin
during its function as an adhesion junction protein. Nemo phosphorylation of β-Catenin alters its effect on rotation and Nemo
thus links the core PCP factors to adherens junction/adhesion
complexes during ommatidial rotation.124
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PCP Effector Genes
Downstream of the core PCP genes, the planar information needs
to be appropriately interpreted. In the eye, the R3/4 cell fate has
to be specified and the PR cluster rotation needs to be executed
8
PCP Effectors in the Wing
inturned (in), fuzzy (fy), fritz (frtz) and multiple wing hairs
(mwh) are the most prominent PCP effector genes in the wing
(the “mwh group” of genes; reviewed in ref. 128). Fy is a fourpass transmembrane protein, while In and Frtz are cytoplasmic
proteins, the latter containing WD40 repeats. Mwh contains
a potential Rho family GTPase binding domain (GBD) and a
Formin Homology 3 (FH3) domain.129,130 FH3 domains are usually implicated in the autoinhibition of formins, a class of proteins
able to catalyze the polymerization of linear actin filaments.131 In
flies, in, fy and frtz genetically act upstream of mwh and downstream of the core PCP genes.128 In core PCP mutants, a single
actin hair emerges from the center of a cell with aberrant polarity, while in mwh group mutants, several hairs emerge per cell.
Interestingly, Inturned localizes to the proximal apical domain
Organogenesis
Volume 7 Issue 3
of wing cells as do Stbm and Pk and this asymmetric localization
depends on the core PCP genes. Membrane localization of In, per
se, is dependent on fy and frtz and all three proteins are required
for the membrane proximal enrichment of Mwh.129,132,133 While
the core PCP genes provide proximal and distal cues for actin hair
initiation, Mwh initially inhibits apical pimple formation on the
proximal side of the wing cell.129,130,133 Later, as its name suggests,
Mwh prevents the formation of additional hair shafts next to the
prehair.129,130 Based on the domain composition of Mwh with its
similarities to formins (but lacking their characteristic catalytic
domain), it is tempting to speculate that Mwh could directly
interfere with actin polymerization. For example, its GBD could
compete for active Rho GTPases and thus dampen the activation of formins. Alternatively, as FH3 domains of formins can be
involved in autoinhibitory intramolecular interactions with the
catalytic FH2 domain, one could also envisage a function of the
FH3 domain of Mwh as a natural dominant negative version of a
formin. However, in contrast to vertebrates, in which the DAAM
family of formins has been shown to be required for PCP signaling (by bridging Dsh and RhoA), mutations in its Drosophila
ortholog show no PCP related phenotypes.134
It is also worth mentioning that Drok and RhoA mutants produce strong wing hair defects.116,135 However, their roles in “PCP
signaling” may in part reflect their general function in actin biology. Nevertheless, RhoA appears to have multiple and more complicated functions during wing hair formation.135
It has recently become clear that more basic cellular processes
affect PCP signaling as well. For example, the interaction between
Dsh and Fz is affected by an additional interaction of Dsh with
lipids in the plasma membrane. This electric charge based interaction is modulated locally by the Na+/H+ exchanger Nhe2.136
Furthermore, it has recently been shown that the Prorenin receptor (PRR), a component of the major vATPase is required for
proper convergence and extension in Xenopus and for PCP signaling in Drosophila137-139 (although in this case, the effect is not
specific for PCP signaling as it also affects canonical Wnt signaling; reviewed in ref. 140). Thus local pH effects either at the
plasma membrane or in early endosomes cannot only specifically
affect PCP signaling, but also Wnt signaling more generally.
example, ft and fj clones lead to a non-autonomous phenotype
similar to fz with posterior hair inversion on the abdomen and
polar chirality inversions in the eye.49,51,53,72,149 In contrast, ds
clones induce non-autonomous effects on the anterior and equatorial side of the abdomen and eye, respectively. Atrophin (Atro),
a transcriptional repressor able to interact with the intracellular
C-terminus of Ft, has the same genetic requirements as ft, and
atro mutations cause ft-like non-autonomous phenotypes in the
eye, suggesting mechanism for the Ft/Ds system involving transcriptional control.150
In contrast to Ft, which is expressed evenly across the tissue, Ds and Fj are expressed in opposing gradients in the wing
and eye, with Ds highest toward the poles of the eye and at the
(proximal) hinge of the wing, and Fj declining from the equator and the distal wing tip.53,142,145,151 It was thus suggested that
the Ft/Ds system provided the missing graded input into the core
PCP system, an idea that more recently has been strongly challenged.49,50,152 Based on the graded expression of Ds and Fj and
the clonal analysis in the eye, it was postulated that graded Ft
activity leads to graded activation of Fz and the core PCP factors. Specifically, during R3/4 fate specification, wild-type cells in
ommatidia genetically mosaic for ft or fj with respect to R3/4 will
(almost) always become the R3 cell, while the mutant cell is specified as R4. Since this “fate pushing” activity appears to require
fz function,53 the Ft/Ds system was placed upstream of the core
PCP system. Consistent with this, an artificially inverted Ds gradient in the eye (in a ds, fj double mutant background) can largely
invert the planar polarity across the whole eye field, apparently
reinstructing (or overriding) the core PCP system.153 In addition,
the non-autonomy of fz is reverted in ds mutant wings and the
Ds system can thus, at least in some instances, control the core
PCP system.141 Consistent with this notion, the domineering nonautonomy induced by Fz overexpression is increased in ft clones142
and Ft/Ds regulate the alignment and polarity of the microtubules in the wing along which Fz containing vesicles travel.106,107
However, several lines of evidence indicate this hierarchy
should be questioned. First, uniformly flat expression of Ds and
Fj rescue (most) of the PCP defects of ds, fj double mutant wings
(note, however, that in the eye, flat Ds can rescue a ds mutant,
but only if fj is normal).151,153 Most importantly, data from studies
of the abdomen clearly demonstrate that, at least in this tissue,
the Ft/Ds and the core PCP systems are independent.18,49,50,110 For
example, a ft clone still induces the same non-autonomous effects
in a fz mutant background as in wild-type. Analogously, overexpression of Ft or Ds (lacking its intracellular domain) in a fmi, fz
double mutant background (thus eliminating all core PCP activity) is able to repolarize trichomes as in a wild-type background,
showing that the two systems can act independently.49 Future
research to identify downstream components of the Ft system is
required to mechanistically explain how Ft affects planar polarity or to account for tissue-specific differences.
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The Ft/Ds System
Fat (Ft) and Dachsous (Ds) are cadherins that control proximaldistal patterning and cell growth and also regulate PCP. ft and
ds mutants cause PCP defects in the wing, abdomen and eye.5053,72,110,141
Ft and Ds form heterotypic interactions across cell
membranes142 and their affinity can be regulated by the golgi
resident, luminal (i.e., ultimately extracellular) kinase Fourjointed (Fj).54,143-145 Phosphorylation of the extracellular domain
of Ft by Fj increases its affinity for Ds, while phosphorylation of
Ds decreases its affinity for Ft, suggesting that Fj polarizes the
strength of a Ft/Ds interaction146,147 (however, this interpretation
is oversimplified, as a Ft lacking the extracellular domain can
rescue a ft mutant; reviewed in ref. 148).
Loss of the Ft/Ds system in clones leads to striking non-autonomous PCP defects in the abdomen, eye and wing.51-53,72,141,149 For
Conclusions
Significant progress has been made in recent years toward our
understanding of how of PCP is established and how initial
www.landesbioscience.comOrganogenesis
9
polarity cues are interpreted to produce polarized, tissue-specific
responses. Many of the initial observations made in flies appear
to be conserved in vertebrates (see related reviews in this issue).
Nevertheless, pressing questions remain. Probably the most
intriguing point that needs to be addressed in the future is how
Fz/Stbm activities are regulated. The observation that PCP signaling is Wnt-independent in flies in contrast to vertebrates
remains truly puzzling. Furthermore, downstream components of
the Ft/Ds system need to be identified in order to understand how
that system is integrated with the action of the core PCP system,
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Organogenesis
Volume 7 Issue 3
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Organogenesis
Volume 7 Issue 3
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