REVIEW ARTICLE
Diego and friends play again
Old planar cell polarity players in new positions
Jo
´
zsef Miha
´
ly, Tama
´
s Matusek and Csilla Pataki
Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary
Functional tissues are comprised of polarized cell
types. Cellular polarization can be manifested in
many different ways, depending on the orientation
and axis of polarity. Well known examples include
the Drosophila ovary and embryo, where all major
body axes are determined in a single cell; neuronal
cells that typically exhibit axonal-dendritic polarity
and epithelial cells that are characterized by apical-
basal polarity. In many instances, however, tissue dif-
ferentiation also requires the coordination of cell
polarity within the plane of a tissue – a feature
referred to as planar cell polarization (PCP) or tissue
polarity for short. Although PCP can be observed
throughout the animal kingdom (vertebrate examples
include fish scales, bird feathers and hairs in mam-
mals, or the neurosensory epithelium in the inner
ear), the regulation of such coordinated cell polariza-
tion events has been best studied in the fruitfly, Dro-
sophila melanogaster.
PCP in flies is most evident in the wing, which is

E-mail:
(Received 21 February 2005, accepted
27 April 2005)
doi:10.1111/j.1742-4658.2005.04758.x
The formation of properly differentiated organs often requires the planar
coordination of cell polarization within the tissues. Such planar cell polar-
ization (PCP) events are best studied in Drosophila, where many of the key
players, known as PCP genes, have already been identified. Genetic analy-
sis of the PCP genes suggests that the establishment of polarity consists of
three major steps. The first step involves the generation of a global polarity
cue; this in turn promotes the second step, the redistribution of the core
PCP proteins, leading to the formation of asymmetrically localized signa-
ling centers. During the third step, these complexes control tissue-specific
cellular responses through the activation of cell type specific effector genes.
Here we discuss some of the most recent advances that have provided
valuable new insight into each of the three major steps of planar cell
polarization.
Abbreviations
MF, morphogenetic furrow; PCP, planar cell polarization.
FEBS Journal 272 (2005) 3241–3252 ª 2005 FEBS 3241
First, a long-range polarity signal is set up. At present,
the molecular nature of this signal is unclear, but it is
believed that the atypical cadherins fat (ft) and dach-
sous (ds), the type II transmembrane protein four-join-
ted (fj) and the transcriptional repressor atrophin (atro)
are all involved in the generation or the modulation of
this long-range positional cue [10–20]. In the second
major step, the core PCP proteins redistribute and
build up asymmetrically localized multiprotein com-
plexes. Finally, these apical membrane-associated

tation and also in this case hairs often form in the
center of the cell instead of the most distal part [29].
Certain other mutations, however, such as in, multiple
wing hair (mwh) and fuzzy (fy) do not affect hair ori-
entation, but result in the formation of multiple hairs
from a single cell [29,30]. Thus, PCP genes appear to
regulate three major aspects of wing hair develop-
ment: they restrict wing hair outgrowth to the distal-
most part (distal vertex) of the cell, they control hair
orientation and they determine the number of hairs
produced.
In contrast to the wing, where each individual cell
normally becomes polarized, PCP in the eye is reflected
in the arrangement of a group of cells corresponding
to the unit eyes called ommatidia (Fig. 1C). Each
ommatidium consists of 20 cells including eight photo-
receptor cells and 12 supporting cells. Sectioning of the
adult eye reveals that the ommatidia are chiral struc-
tures as photoreceptor cells aquire an asymmetrical
trapezoidal shape within each of these multicellular
units [31]. Interestingly, the ommatidia in the dorsal
half of the eye all adopt the same chirality, but this is
opposite to that adopted in the ventral half resulting
in a mirror symmetry arrangement (Fig. 1D). The line
where the dorsal and ventral ommatidia meet corres-
ponds to the dorsal–ventral midline, often called the
equator. This spectacular planar organization is settled
during imaginal disc development, a few hours after
the photoreceptor preclusters emerge from the mor-
phogenetic furrow (MF) of the eye-antennal disc. The

can also be observed in the developing eye disc
[16,37,38,40], although it is only in the precursor cells
Planar cell polarity in Drosophila J. Miha
´
ly et al.
3242 FEBS Journal 272 (2005) 3241–3252 ª 2005 FEBS
of the R3 ⁄ R4 photoreceptors where protein relocaliza-
tion takes place leading to a transiently asymmetric
localization. Interestingly, Fz and Dsh become locali-
zed on the R3 side, Stbm and Pk on the R4 side, and
Fmi on both sides of the R3 ⁄ R4 boundary (Fig. 2B).
Thus, the PCP protein distribution at the R3 ⁄ R4
boundary in the eye displays striking similarities to
that of the distal ⁄ proximal cell border in the wing
and hence the R3 ⁄ R4 cell boundary appears to be
functionally equivalent to the distal ⁄ proximal cell
boundary in the wing. Consistent with the protein
distribution in the eye, for fz and dsh there are genetic
requirements in R3 [32], for stbm and pk in R4 [5,41],
and for fmi in both R3 and R4 [37].
It has been demonstrated that all the PCP proteins
are required for the correct localization of each of the
others, suggesting that these molecules might act
together in a multiprotein complex. However, detailed
phenotypic analysis in the wing and eye has revealed
that the different proteins might play different roles in
the process of PCP protein localization. In the wing,
this is suggested by the fact that, while some PCP
mutations (e.g. fmi) impair the apical localization of
the other proteins, others (e.g. dsh) merely affect the

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Fig. 1. Planar polarity and PCP phenotypes in the wing and eye. (A) The establishment of PCP in the wing begins with actin accumulation at
the distal vertex (middle cartoon) that will subsequently lead to the formation of a distally pointing hair (shown in green). (B) The absence of
PCP genes can affect hair formation in different ways. Hairs are sometimes disoriented, and the site of hair outgrowth is often not restricted
to the distal most part of the cell, or multiple hairs form in a single cell (mutant forms are indicated in red). (C) Ommatidial preclusters
emerge from the morphogenetic furrow (MF) of the eye disc and initially form symmetric structures. As eye development proceeds preclus-
ters rotate 90° towards the equator, i.e. dorsal clusters rotate clockwise, while ventral ones rotate counterclockwise. At the end of this pro-
cess the R3 ⁄ R4 cell pair acquires an asymmetric position within the cluster, and thus chirality also becomes established (R3 cells are
highlighted in green, R4 cells in red). (D) The mirror symmetric structure of an adult eye can be disrupted by PCP mutations that can cause
rotation defects, dorsal-ventral inversions, and loss of chirality resulting in symmetrical ommatidia with either R3 ⁄ R3 or R4 ⁄ R4 cell pairs (see
enlarged on E).
J. Miha
´
ly et al. Planar cell polarity in Drosophila
FEBS Journal 272 (2005) 3241–3252 ª 2005 FEBS 3243
two main phases: proteins first become localized to
adherens junctions in the apicolateral membrane, and
in the second stage they become asymmetrically distri-
buted along the proximal–distal axis in the case of the

model in which at least Dsh and Pk become apicolater-
ally localized due to direct binding to Fz and Stbm.
Because in the absence of Dsh, Pk or Dgo, apicolateral
recruitment of the other PCP proteins is not affected,
but their asymmetric redistribution does not take place
[9,42] (Table 1), it seemed reasonable to assume that,
although Dsh, Pk and Dgo play negligible roles in
apicolateral recruitment, they are required to promote
the assembly and ⁄ or the maintenance of asymmetric
PCP complexes.
An interesting recent paper [26] has now questioned
this simple interpretation and presented new insight
into the mechanisms regulating the initial apical local-
ization and subsequent maintenance of PCP com-
plexes. The research in this paper is focused on dgo,
the least well characterized core PCP gene. Previous
work has shown that Dgo is colocalized with Fz and
Fmi during polarity establishment in the wing, and
apical Dgo localization depends on these proteins [9].
At that time, however, it was not possible to determine
the precise subcellular localization of the dgo gene
product. Das et al. have now reported that Dgo accu-
mulates on the distal side of the wing cells. Not sur-
prisingly, in the eye Dgo becomes enriched on the R3
side of the R3 ⁄ R4 cell boundary, and it follows that,
just like fz and dsh, dgo is genetically required in R3.
2
3
4
5

5
8
2
3
4
5
8
Fig. 2. Core PCP protein localization in the developing wing and
eye. (A) During the initial phase of pupal wing development [up to
 24 h after prepupa formation (APF)] the protein products of the
core PCP genes are found in apically localized symmetric com-
plexes (shown on the left). However, at  24 h APF they redistrib-
ute into asymmetric complexes that are present transiently until
actin accumulation begins at  32 h APF. Between 24 and 32 h
APF Fz, Dsh and Dgo are enriched on distal cell membranes, Stbm
and Pk accumulate on proximal membranes, while Fmi is found on
both sides (right panel). (B) Although core PCP protein localization
in the eye is somewhat more complicated than in the wing, it
appears that PCP protein distribution across the R3 ⁄ R4 cell bound-
ary is remarkably similar to that of the distal–proximal cell boundar-
ies in the wing. Notably, after the initial phases of ommatidia
differentiation when PCP proteins do not show polarized accumula-
tion, five or six rows behind the morphogenetic furrow Fz, Dsh and
Dgo begin to preferentially accumulate on the R3 side, whereas
Stbm and Pk accumulate on the R4 side, and Fmi becomes
enriched on both sides of the R3 ⁄ R4 interface. Developing ommati-
dia are shown in five-cell precluster stages before and after asym-
metric redistribution takes place, Row 4 and Row 7, respectively.
Color code of the PCP proteins is identical in both (A) and (B). Num-
bers on (B) indicate the identity of the photoreceptor precursor

mutant clones Dgo is much reduced at the apical cor-
tex. Significantly, it has also been revealed by yeast
two-hybrid and GST pull-down assays that Dgo inter-
acts physically with Pk and Stbm.
These results suggest that, opposite to what might
be expected from single mutant analysis, Pk and Dgo
are also required for membrane localization of the
PCP factors, though this is a redundant requirement
between Dgo, Pk and Stbm. These data led Das et al.
[26] to outline a model to explain how PCP complexes
might be formed and maintained during the early
phases of PCP establishment (Fig. 3B). They propose
that the cytoplasmic PCP proteins (Dsh, Dgo and Pk)
initially recruited to the membrane by Fz and Stbm
form a protein complex that is required to maintain
Fmi apically. In turn, apical Fmi promotes the main-
tenance of the PCP complex at adjacent cell mem-
branes and can also facilitate their signaling specific
interactions. This model is consistent with the available
data and also supported by the protein–protein inter-
action results. However, in so far as Fmi is concerned,
Das et al. came to just the opposite conclusion to that
of Bastock et al. who suggested that Fmi lies at the
top of the hierarchy of apical PCP protein recruitment
[42]. In that view, Fmi is required for the initial mem-
brane recruitment of Fz and Stbm (Fig. 3A). While
these opposing views might simply reflect tissue-specific
differences between the eye and the wing, an fz, stbm
double mutant analysis could be informative in respect
of the order of initial membrane recruitment. If Fmi is

B
Fig. 3. Two possible models of apical PCP protein recruitment. (A) One model, mainly based on data in the wing, proposed that Fmi lies on
the top of the hierarchy of apical recruitment, and it is responsible for recruiting Fz and Stbm (top panel). Subsequently, these membrane
proteins would recruit the putative cytoplasmic proteins, Dsh, Dgo and Pk (bottom panel). (B) The second model, based on eye data, sug-
gests that Fz and Stbm would be the initial membrane recruiters of Dsh, Dgo and Pk (top panel), and these proteins would then be required
to maintain Fmi apically (blue arrows, bottom panel). In turn, Fmi would promote the maintenance of the whole core PCP complex at adja-
cent cell membranes. Black arrows represent the genetic requirements for apical recruitment, grey ovals indicate the nuclei. (A) and (B) are
modified figures after Bastock et al. [42], and Das et al. [26], respectively.
J. Miha
´
ly et al. Planar cell polarity in Drosophila
FEBS Journal 272 (2005) 3241–3252 ª 2005 FEBS 3245
by Das et al.), apical Fmi should be lost in the fz, stbm
double mutant clone. In fact, in the wing, unlike the
situation in the eye, stbm moderately reduces the level
of apically localized Fmi and fz also has a weak effect,
which could be used as an argument in favor of Fmi
localization being dependent on Fz and Stbm. Such
simple assumptions, however, must be treated with
caution because one of the limitations of the genetic
approaches used during these experiments is that they
do not clearly distinguish between initial apical recruit-
ment and maintenance. At present therefore it is not
possible to distinguish between the two alternatives
that have been put forward to explain the apical
recruitment and maintenance of PCP complexes.
Moreover, as we know very little about the molecular
composition of the PCP complexes formed in vivo and
the feedback mechanisms that might help to stabilize
them, it is clear that other models are also possible.

associated protein, Four-jointed
A few hours after PCP proteins have been recruited to
the apicolateral regions, they become asymmetrically
distributed. How does this happen? Although the
answer to this question is largely unclear, it is believed
that redistribution occurs in response to a directional
signal that coordinates polarity with the axis of the tis-
sue. It is also generally thought that the polarity signal
induces a bias in Fz activity along the proximal ⁄ distal
axis of the wing and the equatorial⁄ polar axis of the
eye [16,18,36]. Subsequently, the initially created subtle
difference in Fz activity on the opposite sides of the
cells would be amplified by intercellular feedback
mechanisms, leading to high Fz signaling on the distal
(i.e. in the wing) and equatorial (i.e. in the eye) sides,
and to low level signaling on the opposite sides [39].
While this is an attractive model, there are several
important points that need to be verified. It is not yet
clear what the link is between differential Fz activation
and asymmetric redistribution. What is the cause and
what is the consequence here, if there is a direct casual
relationship at all? Another important problem is that
the source and nature of the polarity signal remain elu-
sive, including the important question of whether it is
a long-range or a short-acting signal. Models based on
the former possibility propose that polarity is estab-
lished as a result of interpreting the concentration of a
long-range signal (most probably a secreted factor)
present in a concentration gradient across the tissue.
Alternatively, a locally acting short-range signal could

ing of the signaling events between these proteins and,
potentially, other pathways and proteins; and there is
a need to learn more about the molecular biology and
biochemical properties of these proteins. Some pioneer-
ing experiments have already provided evidence that ft
acts through the transcriptional corepressor Atro [17],
support for the in vivo existence of a Ft–Ds hetero-
philic interaction [19], and last but not least, revealed
that Fj is a Golgi-associated protein [27].
Former studies demonstrated that fj is expressed in
a gradient in the developing wing and eye [11,12], and
that clones of cells which either lack or ectopically
express Fj cause both autonomous and nonautono-
mous PCP defects in these tissues [11,12]. Additionally,
an in vitro analysis has indicated that the extracellular
C-term of the Fj protein can be cleaved, resulting in a
secreted form [47]. Together, these results strongly sug-
gested that Fj functions as a secreted signaling mole-
cule present in a gradient on the proximo–distal axis
of the wing and the dorso-ventral axis of the eye.
Strutt et al. have now tested this idea directly by com-
paring the signaling abilities of modified Fj forms that
are either poorly cleaved, constitutively secreted or
anchored to the Golgi [27]. During this elegant set of
experiments, they used overexpression and rescue
assays to test the in vivo activities of the different Fj
forms and concluded that secreted Fj is not the active
form, but, unexpectedly, Fj acts intracellularly. This is
consistent with their antibody staining result that most
Fj is localized to discrete spots inside the cells, the

phenotypes when homozygous [10,14,16], while fj dis-
plays polarity phenotypes almost only on the boundar-
ies of mutant clones [12], the weak fj phenotype was
explained by redundancy. However, the origin and
nature of this redundancy remain uncertain, largely
because of the lack of information on the molecular
function of fj. In the light of recent data, it may be spe-
culated that, while Fj modulates Ft ⁄ Ds activity, for
example, by adding certain type of post-translational
modifications on it, full Ft⁄ Ds activity would require
additional upstream inputs (e.g. additional types of
post-translational modifications). Thus, Fj activity
would contribute to the activation of Ft ⁄ Ds, but alone
it would not be sufficient to create a fully functional
form. As a consequence, the absence of Fj would be
compensated by additional, an as yet unidentified fac-
tors also involved in Ft ⁄ Ds modulation.
Although the precise mechanisms by which these ele-
ments contribute to the formation of global polarity
cues have not been fully clarified, experiments of this
type offer promising new developments in the PCP
field, and underline the importance of biochemical
approaches in elucidating further details of PCP estab-
lishment.
Inturned: a new turn in the game
While much attention has recently been paid to the
asymmetric localization of the PCP proteins and to
the mechanisms of action of the potential upstream
elements, novel studies on inturned (in), a planar
polarity effector gene, have led to the discovery of a

an interaction is still possible, another alternative
would be that Fuzzy (Fy) or Fritz (Frtz) or both are
involved in In recruitment and localization. This
would be consistent with several different findings.
First, asymmetric In accumulation and In protein sta-
bility have both been shown to depend on fy and frtz
[28]. Second, although it has not been studied in
detail, fy appears to encode a transmembrane protein
that could recruit In directly [51]. Third, single or
double mutants of fy, frtz and in display almost iden-
tical wing hair phenotypes [29,52], suggesting that
these genes function together in PCP and might inter-
act with each other directly. As we know very little
at the molecular level about Fy and Frtz, and their
subcellular localization has not been described yet, In
recruitment remains an open issue. We note, however,
that the combination of the above alternatives is also
a valid possibility. In that scenario, Stbm and ⁄ or Pk
would be the key to the initial proximal recruitment
of In or Fy or Frtz, which in turn would promote
the assembly of a functional In⁄ Fy ⁄ Frtz complex.
Previous observations have suggested that the spatial
restriction of cytoskeleton activation and prehair for-
mation to the distal vertex of the wing cells largely or
entirely depends on the local (distal) accumulation and
activation of Fz and Dsh, whereas the proximal accu-
mulation of other PCP proteins has been only sugges-
ted to play a role in the establishment of proximal and
distal cortical domains. It has now been found that
local Fz ⁄ Dsh signaling alone is not sufficient to restrict

time Stbm ⁄ Pk inhibits hair formation in the proximal
part, acting through an In complex. Thus, this model
predicts that the restriction of hair outgrowth exclu-
sively to the distal vertex of the cell requires that the
positively acting distal Fz ⁄ Dsh PCP signal is paralleled
by an In inhibitory signal on the opposite side of the
cell that might form an intracellular gradient with its
high end at the proximal pole. Interestingly, this hypo-
thesis may help to explain a previously described set of
results that were difficult to reconcile with a simple lin-
ear regulatory relationship between the core elements
and the in-like genes. Notably, Lee and Adler reported
that a weak multiple wing hair phenotype induced by
hypomorphic in or fy alleles is strongly enhanced both
by the removal and by the overexpression of fz, fmi or
dsh [52]. If we consider that, in the absence of fz, the
site of actin accumulation is already somewhat ‘delo-
calized’, leading to a weak multiple hair phenotype,
the inhibitory model predicts that the introduction of
a hypomorphic in allele into this background will
enhance the multiple wing hair phenotype, because the
proximally acting inhibitor of cytoskeleton activation
is also impaired. This prediction fits perfectly with the
published data. If we now consider the case of Fz
overexpression, we find that the excess of Fz induces a
failure in asymmetric PCP protein redistribution, lead-
ing to an imperfect restriction of actin accumulation
even in the presence of In (which itself fails to undergo
proper localization in this situation). If Fz overexpres-
sion is accompanied by a parallel impairment of the

additional valuable insights, however, it is equally clear
that genetic and cell biological methods must be com-
bined with biochemistry in order to reach the heart of
these problems. A detailed biochemical characteriza-
tion of the core group may allow a functional dissec-
tion of the process. Moreover, we need a better
understanding of the protein–protein interactions
between the core elements, we need to describe the
complexes formed in vivo, and we need to learn about
their spatial and temporal regulation during PCP
establishment.
A second area of PCP research that has recently
received considerable attention is the generation of
long-range polarity cues. While much has been learnt,
the mysterious story of factor X continues, as the exact
nature, source and mode of action of the polarity sig-
nal are still unknown. Interestingly, however, import-
ant new results (not discussed in this minireview) have
led to the identification of further upstream elements,
one of which (widerborst) is asymmetrically localized
J. Miha
´
ly et al. Planar cell polarity in Drosophila
FEBS Journal 272 (2005) 3241–3252 ª 2005 FEBS 3249
long before the redistribution of the core elements [53],
while the other (encoded by the grainy head transcrip-
tion factor) is indirectly required for the apical local-
ization of the core PCP proteins via the regulation of
fmi transcription [54]. These findings tend to lead us to
question the view that asymmetric core PCP protein

´
nos Research Scholar, and supported by an NIH
FIRCA grant, and EMBO ⁄ HHMI.
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