Department of Zoology, University of Wisconsin, 250 North Mills Street, Madison, WI 53706, USA
* Author for correspondence (e-mail: ssblair{at}wisc.edu)
Accepted 29 April 2004
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SUMMARY |
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Key words: Adhesion, Cadherin, Frizzled, Drosophila
![]() |
Introduction |
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In PCP, cells of an epithelial sheet are polarized perpendicular to the
apical-basal axis (Adler, 2002;
Eaton, 2003
;
Fanto and McNeill, 2004
;
Strutt, 2003
;
Uemura and Shimada, 2003
). In
the Drosophila wing, the hairs produced by each epithelial cell
normally point distally (see Fig.
3A). In one view, PCP in the wing relies in part upon signals
passed from cell to cell via the Frizzled (Fz) PCP pathway, using the `core'
planar polarity proteins (Fig.
1E) (Tree et al.,
2002
). From 18-30 hours after pupariation (AP), the core planar
polarity proteins are redistributed to the proximal [Prickle (Pk), Van Gogh
(Vang, also known as Strabismus)], distal [Fz, Dishevelled (Dsh)], or proximal
and distal [Flamingo (Fmi), also known as Starry night] faces of individual
cells (Axelrod, 2001
;
Bastock et al., 2003
;
Shimada et al., 2001
;
Strutt, 2001
;
Tree et al., 2002
;
Usui et al., 1999
). This
redistribution requires mutual interactions between these proteins, both
within and between cells. The interaction between cells is thought to ensure
that neighboring cells have a similar polarization.
|
|
|
Another mechanism for regulating Ft activity may be provided by the
distally expressed Four-jointed (Fj) protein
(Fig. 1B,C,E)
(Brodsky and Steller, 1996;
Villano and Katz, 1995
;
Zeidler et al., 2000
). Like
ds and ft mutants, null alleles of fj cause
proximodistal defects in wing and leg. Although fj null homozygotes
have little effect on PCP, creating artificial boundaries or gradients of
fj expression can alter PCP, suggesting that it acts as a redundant
cue (Zeidler et al., 1999
;
Zeidler et al., 2000
). Clones
lacking fj affect anti-Ft and anti-Ds staining in a manner consistent
with a reduced interaction between Ds and Ft
(Ma et al., 2003
;
Strutt and Strutt, 2002
).
Recent evidence indicates that Fj acts in the Golgi, suggesting that Fj
affects the interaction between Ft and Ds by modifying the forms generated or
the cellular localization of these proteins
(Strutt et al., 2004
).
The Ft-Ds signaling model is based on loss-of-function phenotypes, as the
very large size of these molecules has made the construction of misexpression
constructs difficult. We have, however, developed fully functional constructs
for the misexpression of full-length Ft and Ds, and we use these to test
various predictions of the model. First, Ft and Ds must bind preferentially.
Although the changes in protein distribution caused by loss-of-function clones
are consistent with a heterophilic interaction
(Ma et al., 2003;
Strutt and Strutt, 2002
), this
has never been directly demonstrated. We show that Ft and Ds mediate
preferentially heterophilic cell adhesion in vitro and in vivo. Second,
artificial gradients of ft and ds expression in the wing
should be sufficient to reorient PCP throughout the wing; again, we show that
this prediction is largely met.
The extensive PCP defects induced by loss of ds suggest that the gradient of ds expression acts as a global cue required for orienting PCP throughout the wing. However, it remains possible that ds acts, not as an instructive cue, but as a permissive factor, and that the crucial polarity information is being provided other cues. We have therefore tested the role of the ds gradient by driving uniform ds misexpression. Surprisingly, we find that a gradient of ds is not necessary for correct PCP in all but the most proximal region of the wing. In most of the wing, uniform ds expression can rescue the ds mutant PCP phenotype. This is true even in the absence of any putative redundant information from Fj. Thus, other unknown cues are sufficient to orient PCP in absence of information from the pattern of ds transcription.
We have also used misexpression to test the timing of Ds activity in PCP,
by analyzing whether Ds acts during the stages when the core polarity proteins
are being redistributed, or whether it acts during an earlier, recently
identified period of Fz activity (Strutt
and Strutt, 2002). If the loss of fz is limited to this
early period, distinct PCP defects are produced that are similar to those
observed in ds mutants, but differ from the typical PCP defects
observed in fz mutants. Because of this similarity in phenotypes, it
was suggested that Ds acts during this early period
(Eaton, 2003
;
Strutt and Strutt, 2002
). Our
data supports this hypothesis.
Finally, we show that Ft misexpression is sufficient to drive PCP in an orientation opposite that that caused by Ds, and that the activity of ectopic Ft depends partly, but not wholly, on the presence of Ds and Fj.
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Materials and methods |
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Molecular biology
UAS-ds contains the full-length ds coding sequence,
reconstructed from fragments amplified by RT-PCR (Takara). UAS-ft
contains full-length ft genomic sequence, reconstructed from DNA
fragments obtained from P1 clones DS06482 and DS06843, or amplified from
genomic DNA by PCR. All constructs were confirmed by sequencing and cloned
into pUAST (Brand and Perrimon,
1993). Detailed information is available by request. To induce
expression in S2 cells, we co-transfected UAS-ft or UAS-ds
with pAWGal4 (gift from Y. Hiromi), which drives Gal4 under the control of an
actin promoter in S2 cells. To examine the effects of ft or
ds misexpression in vivo, UAS constructs were injected into
w1118 embryos and transfectants were isolated using
standard methods. In western blots of transfected S2 cells, we detected bands
corresponding to full-length and processed Ft and Ds proteins (data not
shown); each construct can substantially rescue the PCP defects of the
corresponding mutant.
In vitro studies
S2 cells were co-transfected with UAS constructs and pAWGal4. To identify
transfectants UAS-GFP was co-transfected into S2 cells. Cell aggregation
assays were performed as described (Usui
et al., 1999; Oda et al.,
1994
). Cells were normally agitated on a rotator at 50 or 100
rotations per minute (rpm); 150 rpm was used for high rates of agitation.
Immunostaining
S2 cells were fixed in 4% formaldehyde in PBS for 30 minutes at room
temperature, with rhodamine-labeled phalloidin (Molecular Probes, 1:2000)
added as a counterstain. Wing discs and pupal wings were fixed in 4%
formaldehyde in Brower fix buffer lacking EGTA at room temperature for 40
minutes. The following primary antibodies were used: rat anti-Ds (1:20,000)
(Yang et al., 2002), rabbit
anti-Ds (1:100) (Strutt and Strutt,
2002
), rat anti-Ft (1:2000)
(Yang et al., 2002
), mouse
anti-DSRF (Geneka, 1:1000), rabbit anti-pMad (1:2000)
(Tanimoto et al., 2000
) and
mouse anti-ßgal (Developmental Studies Hybridoma Bank, 1:1000).
Fluorescent secondary antibodies were visualized using a Biorad MRC 1024
confocal microscope.
Timed induction of patterned ds misexpression
sal-gal4/tub-gal80ts; UAS-ds/+
embryos or white prepupae were collected and reared at either 20°C or
30°C. Larvae or pupae were upshifted to 30°C or downshifted to
20°C to induce or repress ds expression, respectively. For each
time span we scored more than fifty adults for temperature shifts before
pupariation and more than sixteen adults for temperature shifts at or after
pupariation.
![]() |
Results |
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|
These changes in protein stability and distribution are consistent with our
own and previously reported results from ft-,
ds- and ds- ft- double
mutant clones (Ma et al.,
2003; Strutt and Strutt,
2002
) (data not shown). In the wing pouch Ds is reduced in
ft- clones, whereas Ft is more diffuse (although the
overall staining is elevated) in ds- clones. Moreover, Ft
and Ds are redistributed at mutant clone boundaries in a manner consistent
with the capping of proteins on the cell surface. For example, wild-type cells
at the boundaries of ds- ft- double mutant
clones lose both anti-Ft and anti-Ds staining on the surface facing the clone
(Ma et al., 2003
). Thus, both
the in vitro and in vivo results indicate a preferentially heterophilic
interaction between Ft and Ds. This type of binding is unusual for cadherin
family members, and is consistent with the ligand-receptor relationship
proposed by the signaling model.
Patterned Ds expression is sufficient to reorient PCP and Fz redistribution
To test whether Ds is sufficient to reorient PCP in the wing, we used the
UAS-GAL4 system to drive patterned UAS-ds expression. We observed PCP
defects if we used drivers that drove expression in the spalt
(sal) pattern, which forms a gradient orthogonal to the proximodistal
axis of the wing (Fig. 3B,E).
Similarly, misexpressing ds in the Distal-less
(Dll) pattern, which forms a distal to proximal gradient that is
opposite to the endogenous ds expression pattern, partially reversed
hair polarity (Fig. 3C). The
defects were similar to those caused by misexpressing fz using
dll-gal4 (Adler et al.,
1997) or sal-gal4
(Fig. 3F). PCP defects could
also be induced by creating sharp boundaries of ds misexpression,
using either the posterior-specific driver engrailed (en)
(Fig. 4B) or patched
(ptc), which is expressed at high levels in cells just anterior to
the fourth longitudinal vein (data not shown). en-gal4 and
ptcgal4 induced PCP defects in wild-type tissue adjacent to the
region of misexpression. Similar non-autonomy was found surrounding
ds mutant clones, indicating that the PCP defects are propagated to
adjacent cells (Adler et al.,
1998
; Ma et al.,
2003
; Strutt and Strutt,
2002
). Thus, an artificial gradient or boundary of Ds
misexpression can alter wing hair polarity.
|
Correct PCP in the absence of a Ds gradient
The data above indicate that Ds is sufficient to reorient PCP. However,
that does not test whether the endogenous gradient of Ds is required for PCP.
We therefore used strong misexpression of ds to override the
endogenous ds pattern and create wings with uniform ds
expression. We used either Gal4 driven from a tubulin promoter
(tub-gal4), looked at the posterior of wings with
posteriorly-expressed engrailed (en)-gal4, or
looked at dorsal wings with dorsally-expressed apterous
(ap)-gal4.
Wing PCP was largely unaffected by the presence of uniformly misexpressed ds (tub-gal4, Fig. 4C; posterior of en-gal4, Fig. 4B; dorsal of ap-gal4, data not shown). This was true even though the levels of anti-Ds staining being driven were at (en-gal4, Fig. 2K) or well above (tub-gal4, Fig. 4F; compare with Fig. 4E) the high levels observed in the proximal regions of the wild-type wing. To rule out the possibility of signaling from the endogenous Ds, we repeated these experiments in a ds05142 mutant background, which has a strong PCP phenotype (Fig. 4A) and lacks detectable cell surface anti-Ds staining. Uniform misexpression of Ds (tub-gal4 or posterior of en-gal4) almost completely rescued the ds05142 PCP phenotype distal to the anterior cross vein, without inducing any additional PCP defects (Fig. 4D,H, and data not shown). Thus, distal to the anterior cross vein, PCP must depend on cues other than the pattern of ds transcription.
We were unable, however, to rescue ds05142 PCP defects in the most proximal regions of the wing (Fig. 4D,J). This is the region of the wing that normally has high Ds expression at 5 hours AP (Fig. 1A-C), and thus may require higher levels of Ds activity than could be supplied by misexpression. However, as noted above, the levels of anti-Ds driven using tub-gal4 were well above normal proximal levels (Fig. 4E,F). Moreover, raising the temperature at which the larvae were reared to 30°C, which results in higher activity of the cold-sensitive Gal4, did not reduce the proximal PCP phenotype (data not shown). As there is also a sharp gradient of Ds expression at the distal boundary of this expression domain (Fig. 1A-C), we favor an alternative explanation, that the Ds gradient observed here is locally required for normal PCP (see Discussion).
The Fj gradient plays only a minor role in PCP
What orients PCP in the more distal portions of the wing? One redundant cue
suggested by previous studies is the distally expressed Fj
(Fig. 1B,C). As discussed
above, Fj may be required in vivo for strong interactions between Ft and Ds.
Cotransfection of fj into cells co-transfected with ft and
ds did not detectably enhance their aggregation or reduce their
sensitivity to high rates of agitation. This did not appear to be due to
endogenous Fj, as we could not detect Fj in untransfected S2 cells by western
blot. However, subtle quantitative effects would likely be difficult to detect
in this assay. It is possible that S2 cells do not respond to fj in a
normal manner; for instance, if Fj regulates the membrane localization of Ft
or Ds in epithelial cells, this may differ in the non-epithelial S2 cells, as
they lack any obvious apical-basal polarity.
If Fj does modulate Ft-Ds interactions in vivo, a gradient of Fj could spatially regulate the activity of even uniformly misexpressed Ds, accounting for the failure of uniform Ds to disrupt PCP. However, our tests using a null allele of fj indicate that the contribution of fj to wing PCP is minor. ds05142 fjd1 double mutant wings did not show an appreciably stronger PCP defect than that observed in ds05142 wings (Fig. 5A; compare with Fig. 4A). Moreover, uniform misexpression of ds in a fj null background caused only minor PCP defects in the proximal wing (tub-gal4, Fig. 5B; posterior of en-gal4, not shown), and PCP in most of the wing was normal. Overriding the endogenous gradients with simultaneous uniform misexpression of fj and ds had no effect on PCP (tub-gal4, Fig. 5C; posterior of en-gal4, data not shown). Similarly, the PCP defects caused by patterned ds misexpression using sal-gal4 were only slightly more extensive in a fj null background (Fig. 5D,F; compare with Fig. 3B and Fig. 5E). Thus, the wing must have some sources of polarizing information that can act in the absence of a gradient of ds or fj transcription.
|
When we initiated misexpression during larval stages we observed PCP defects. Defects were rare if induction occurred after 0 hours AP (Fig. 6A). Induction at 0 hours AP resulted in scattered ectopic anti-Ds staining at 5 hours AP at 30°C (the equivalent of 6 hours AP at 25°C; Fig. 6D), and strong misexpression at 22 hours AP at 30°C (the equivalent of 24 hours AP at 25°C; Fig. 6E). Thus, PCP was usually normal despite the misexpression of ds during the stage when the polarized redistribution of core polarity proteins occurs (18-30 hours AP at 25°C).
Conversely, if we induced misexpression early but suppressed misexpression beginning in mid-third instar, few PCP defects were induced; however, if we did not begin suppression until later larval or early pupal stages, strong PCP defects were observed (Fig. 6B). If the suppression of misexpression began at 0 hours AP, ectopic anti-Ds staining was still visible at 5 hours AP at 20°C (the equivalent of 4 hours AP at 25°C; Fig. 6F), but was undetectable at 24 hours AP at 20°C (the equivalent of 17-19 hours AP at 25°C; Fig. 6G). Thus, PCP defects were induced despite the apparently normal ds expression during the stage of Fz redistribution.
The effects of Ft misexpression on PCP
As Ft is uniformly expressed in the wing, it is not thought to play an
instructive role in wing PCP. Nonetheless, we used misexpression to answer two
questions raised by the Ft-Ds signaling model. First, is Ft misexpression
sufficient to drive PCP in an orientation opposite that caused by Ds? Second,
how does the activity of ectopic Ft depend on the presence of Ds and Fj?
UAS-ft showed substantial activity in vivo: when driven with a
low-level driver (da-gal4) it rescued the pupal lethality of
ftG-rv/ftfd heterozygotes and showed
substantial rescue of the mutant wing PCP and tarsal segment defects (data not
shown). Unfortunately, driving stronger expression with tubgal4 in
wild-type wings resulted in larval lethality prior to the stage when PCP
defects could be assessed. However, driving ft misexpression with
en-gal4 (posterior) or ap-gal4 (dorsal) was not lethal, and
resulted in strong PCP defects. These defects were observed not only near the
boundaries of misexpression, but also within regions of apparently uniform
misexpression in the posterior or dorsal wing blade
(Fig. 7A,I,J for
en-gal4, Fig. 7B for
ap-gal4). Driving ft expression centrally using
ptc-gal4 also resulted in strong PCP defects
(Fig. 7C,K), as did driving
ft expression in a gradient orthogonal to the proximodistal axis
using sal-gal4 (Fig.
7D,L). Interestingly, all of these PCP defects were observed in a
central region near the two cross-veins. This is also the region that shows
the most common PCP defects in ft mutant clones
(Strutt and Strutt, 2002). As
expected from the Ft-Ds signaling model, which posits high Ft activity in the
distal wing, driving high distal expression with dll-gal4 did not
induce any PCP defects (data not shown).
|
If Ds spatially regulates Ft activity, then the PCP defects induced by uniform ft mixexpression might be reduced by a reduction in Ds levels. Indeed, in a ds05142 background, the posterior PCP defects induced by the posterior expression of ft were weakened (Fig. 7E,M). However, they were not eliminated, despite the absence of detectable cell surface Ds in the ds05142 background, indicating that the misexpressed Ft has substantial activity even in the absence of its putative ligand. Similarly, if Fj normally plays a role strengthening the Ds-Ft interaction, the effects of misexpressing ft should be reduced in a fj- background. As expected, posterior PCP defects were weakened in fj- wings (Fig. 7F,N).
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Discussion |
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Nonetheless, our data also show that the proximal to distal gradient of ds expression is not necessary for PCP throughout the wing, despite the distal defects observed in loss-of-function ds mutants. Instead, our experiments show that uniform ds misexpression can rescue the PCP defects caused by a ds mutation in all but the most proximal portions of the wing. Thus, ds is permissive for PCP in most of the wing, and there must be another polarity cue in the distal wing that is sufficient to orient PCP in the presence of uniformly transcribed ds. Our experiments indicate that this distal cue is not provided by the distally expressed Fj protein: distal PCP is not disrupted either by uniform misexpression of both ds and fj, or by uniform misexpression of ds in a fj null mutant.
It remains possible that the distal cue functions by regulating Ft-Ds signaling. Our studies tested the PCP inputs from the patterns of ds and fj transcription, but unknown factors might post-transcriptionally regulate the forms of Ds or Ft protein produced, or their availability at the cell surface. It also is possible that Ft activity is spatially regulated by binding partners other than Ds. ft mutants have stronger PCP and disc overgrowth defects than do ds mutants, and misexpression of ft still causes PCP defects in a ds mutant lacking detectable cell surface protein.
Alternatively, the cue may be provided by a mechanism that is completely
independent of Ft or Ds. One often-proposed candidate is signaling via the
Drosophila Wnts, especially given their patterned (distal or
marginal) expression (Baker,
1988; Gieseler et al.,
2001
; Janson et al.,
2001
; Kozopas and Nusse,
2002
) and the involvement of the Wnt receptor Fz in PCP.
Vertebrate Wnt7a also helps regulate PCP in the inner ear
(Dabdoub et al., 2003
).
However, although the misexpression of Drosophila wnt4 can disrupt
wing PCP (Lawrence et al.,
2002
), PCP defects have not been reported in Drosophila
Wnt mutants.
Is a Ds gradient required in the proximal wing?
Although a ds gradient is not required for PCP in most of the
wing, it is possible that such a gradient is required locally in the portion
of the wing near and proximal to the anterior cross vein. We were unable to
rescue proximal ds mutant PCP defects with uniform Ds expression, and
our data suggests that this was not simply a failure caused by insufficient Ds
levels. This is the location of a strong proximal to distal boundary or
gradient of endogenous Ds expression at 5 hours AP (see
Fig. 1A-C). Thus, we favor the
view that this sharp Ds gradient acts as a PCP cue in the proximal wing. If
so, this indicates that the cues that orient PCP in the wing are not generally
distributed; rather, the wing may be a patchwork of different regions that
rely on different cues. This would provide a mechanism for locally altering
PCP during evolution without globally affecting polarity in the wing.
Mechanisms
The hypothesis that Ft acts as a receptor and Ds acts as a ligand for PCP
is based, not only on the uniform expression pattern Ft, but also on epistasis
experiments in the eye, where the PCP activity of ds clones appears
to depend on the presence of ft
(Yang et al., 2002). Wing PCP
can also be disrupted by the expression of a truncated form of Ds lacking its
intracellular domain, which is consistent with Ds acting as a ligand (H.M. and
S.S.B., unpublished).
However, we have shown here that misexpressed Ft retains PCP activity in a ds mutant that eliminates detectable cell surface Ds. Thus, Ft activity is apparently not strictly dependent on patterned Ds expression. Again, this is consistent with the greater severity of ft mutant phenotypes compared with ds, and with our finding that uniform misexpression of ft but not ds can cause PCP defects. As we do not have any evidence for homophilic Ft binding, the unbound Ft molecule may have basal PCP activity. Alternatively, low-level homophilic binding or heterophilic binding to some unknown ligand may activate Ft in the absence of Ds.
It is not yet known how Ft-Ds interactions regulate the polarized
redistribution of the core polarity proteins in the older pupal wing. The
cytoplasmic domains of Ft and Ds contain potential regions for ß-catenin
binding (Clark et al., 1995),
and ft and ds mutants can enhance the effects of
ß-catenin (Armadillo) misexpression
(Greaves et al., 1999
).
However, although expression of DE-cadherin in vitro results in a
detectable concentration of Armadillo at the cell membrane
(Oda et al., 1994
), we have
not detected similar effects after expression of ft or ds
(data not shown). Moreover, clones homozygous for a strong armadillo
mutation do not affect PCP (Axelrod et al.,
1998
). It has also been suggested that the cytoplasmic domain of
Ft binds to and changes the activity of Grunge, the Drosophila
homolog of the Atrophin transcriptional co-repressor
(Fanto et al., 2003
), but it
is not known whether this interaction is altered by Ft-Ds binding.
Our studies examining the timing of Ds activity suggest that its effects on
the polarization of the core polarity proteins are likely to be indirect, as
Ds acts before the polarized redistribution of the core polarity proteins
within cells can be detected. Patterned misexpression of Ds at later stages,
during the time of core protein polarization, had no effect on PCP. The period
sensitive to ds misexpression is roughly congruent with the period of
early Fz activity identified by Strutt and Strutt
(Strutt and Strutt, 2002); if
loss of Fz is limited to a period from 6 to 24 hours AP it leads to distinct,
ds-like PCP defects. Thus, early Fz and Ds activity may be linked, or
they may share a common target.
The only known sign of cell polarization during the stages sensitive to Ds
and early Fz activity is the redistribution of the Widerborst PP2A regulatory
subunit from the anterior-proximal side to the distal side of wing cells at
some time between 8 and 18 hours AP
(Hannus et al., 2002).
Reductions in Widerborst activity can disrupt the polarized redistribution of
Fmi and Dsh, suggesting an instructive role. However, Widerborst polarization
is not affected by ectopic Fz expression, making it less likely that
Widerborst polarization mediates early Fz activity.
Heterophilic protocadherins
A final interesting feature of our results is the preferentially
heterophilic binding we observed between Ft and Ds in vitro. This result is
consistent with our own and previous in vivo analyses of protein distribution
within and adjacent to ft and ds mutant and overexpression
clones (Ma et al., 2003;
Strutt and Strutt, 2002
) (this
study). With the exception of the desmosomal cadherins (Chitaev et al., 1997;
Syed et al., 2002
), this kind
of binding is unusual for cadherin-like proteins.
A number of mammalian Fat-like (Fat1, Fat2, Fat3, XP_227060) and Ds-like
(Protocadherin 16, Cdh23) proteins have been identified
(Bolz et al., 2001;
Bork et al., 2001
;
Cox et al., 2000
;
Dunne et al., 1995
;
Mitsui et al., 2002
;
Nakajima et al., 2001
;
Nakayama et al., 1998
;
Ponassi et al., 1999
).
Mutations and knockouts have been examined for a few of these; however,
conjectures about the bases of the mutant phenotypes have largely assumed that
these proteins mediate homophilic cell adhesion
(Bolz et al., 2001
;
Bork et al., 2001
;
Ciani et al., 2003
;
Wilson et al., 2001
). It will
be interesting to see whether the preferentially heterophilic interactions
observed in Drosophila are preserved in similar mammalian
proteins.
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ACKNOWLEDGMENTS |
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