Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA
e-mail: msimon{at}stanford.edu
Accepted 28 October 2004
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SUMMARY |
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Key words: Planar cell polarity, Gradients, Cadherins, Drosophila, Ommatidia, Positional information
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Introduction |
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Much of our knowledge of PCP comes from studies of the Drosophila
wing, where PCP is apparent in the orderly arrangement of the actin hairs that
grow from the distal edge of each cell
(Adler, 2002;
Shulman et al., 1998
). These
studies have shown that the site of hair growth is designated by the presence
of high levels of Frizzled (Fz) signaling activity along the distal edge of
each cell. This polarization state results from a competitive process whereby
adjacent cells compare Fz signaling activity levels across their proximodistal
junctions (Adler et al., 1997
).
An essential feature of this competition is the presence of feedback loops
that amplify any differences in Fz activity between two adjacent cells
(Tree et al., 2002
). As a
result of these feedback loops, the side of the cell-cell junction with a
higher initial level of Fz activity develops stronger Fz signalling, while the
opposing side reduces its Fz activity
(Strutt, 2001
). In this model,
the uniform orientation of wing PCP arises from signals that consistently bias
the Fz competition so that the proximal side of each cell-cell junction always
emerges with elevated Fz levels. The identity of these directional signals is
currently unknown.
Another example of PCP in Drosophila occurs in the compound eye,
where PCP is evident in the orientation of the dorsal and ventral ommatidia,
which are mirror images of each other (Fig.
1A-D) (Wolff and Ready,
1993). To form this pattern, developing ommatidia must sense the
positions of the equator and/or the nearest pole, and polarize in response.
Evidence that ommatidial polarization is mechanistically similar to PCP in the
wing comes from observations indicating that a core group of proteins
essential for PCP in the wing is also required for properly oriented
ommatidial polarity (Adler,
2002
; Shulman et al.,
1998
).
|
Although considerable insight has been gained into the Fz PCP signaling competition, the signals that directionally bias this competition have been more elusive. The key role of Fz in the establishment of PCP originally suggested that the axes of planar polarization in the wing and eye might be specified by Wnt gradients across the tissue. The resulting gently graded activation of Fz across the tissue could be refined by Fz/PCP competition at each cell-cell boundary to generate the final pattern of polarized Fz signaling. However, searches for Wnts with the expected expression patterns, high in the proximal region of the wing and in the equatorial region of the eye, have not identified appropriate candidates.
During a previous study, we proposed an alternate model for orienting
planar polarization in the eye (Yang et
al., 2002). In this model, the role of the long-range diffusible
PCP signals is to generate opposing transcriptional gradients of the cadherin
Dachsous and the Golgi-associated protein Four-jointed
(Fig. 1F). The resulting
gradients of Ds and Fj protein were proposed to regulate the function of the
ubiquitously expressed cadherin Fat (Ft), resulting in the equatorial R3/R4
precursor cell of each ommatidium having a higher level of Ft function than
its polar neighbor. This difference in Ft activity then biases the Fz/PCP
competition between the R3/R4 precursor cells to ensure that the equatorial
cell emerges with the higher Fz signaling state. Similarly, a study of Fj, Ds
and Ft function in the abdomen has suggested that gradients of Fj and Ds
expression may direct planar polarization in that tissue as well
(Casal et al., 2002
).
This model, which was derived from an analysis of the consequences of removing Fj, Ds or Ft function from one of the R3/R4 precursor cells, makes three crucial predictions with regard to the effects of altering the expression patterns of Fj, Ds and Ft. First, because the directional cues for orienting PCP in the eye are proposed to be present in the Fj and Ds expression gradients, the organized pattern of polarization should be lost when both gradients are replaced by ubiquitous expression. Second, reversing the graded pattern of Fj or Ds expression should lead to corresponding reversals of ommatidial polarity. Finally, ectopic expression of Ft in a graded pattern might be able to specify an altered direction of polarization. In this report, I test and confirm each of these predictions. I further show that the remarkable fidelity of PCP in the eye results from the combined action of the Fj and Ds gradients acting through Ft.
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Materials and methods |
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Expression constructs
The UAS-Fj construct used was previously described
(Zeidler et al., 1999). For
Ds, a genomic DNA fragment extending from 35 bp before the translational
initiation codon to the end of exon 2 was linked in frame to a genomic
fragment containing the remaining coding exons and extending 1933 bp beyond
the termination codon. These joined fragments were then placed into the
UAS-containing P-element vector pUASp
(Rorth, 1998
) as a
NotI fragment. The P-element insert used resides on chromosome 3. For
Ft, the genomic region extending from 60 bp before the start codon and
extending 2734 bp beyond the termination codon was placed in pUASp as a
NotI fragment. The P-element insert used resides on chromosome 3.
This transgene efficiently rescues the lethality of ft flies, as
indicated by the recovery of greater than 80% of the expected number of
ftG-rv/ftl(2)fd; TubP-Gal4/UAS-Ft
adults. Complete sequences of the inserted Ft and Ds fragments are available
on request.
Sections and immunohistochemistry
Sectioning was performed as previously described, except that the osmium
steps were omitted (Tomlinson and Ready,
1987). Staining with anti-Ft antibodies was performed as
previously described (Yang et al.,
2002
). Wings were examined after mounting in Euperol.
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Results |
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In order to evaluate the roles of the Fj and Ds gradients, the pattern of ommatidial polarity was examined for various combinations of loss-of-function, ubiquitous expression and wild-type expression of each gene. The animals tested and the resulting phenotypes are summarized in Table 1. Several of the results are crucial to evaluating the roles of the Fj and Ds expression gradients. First, the overall pattern of polarization is retained when either the Fj or the Ds gradient is replaced with ubiquitous expression (Fig. 2E,F). However, in each case, a low rate of polarity errors is observed (Table 1). This contrasts with wild-type eyes in which polarity mistakes are rarely, if ever, observed (Fig. 2A). These findings indicate that neither expression gradient is essential for directing PCP in the eye. However, the occurrence of polarity mistakes suggests that the strength or quality of information is reduced when one gradient is replaced by ubiquitous expression. By contrast, the replacement of both gradients with ubiquitous expression results in the complete loss of organized PCP, as indicated by a randomized pattern of polarity in which dorsal and ventral type ommatidia are mixed together without an obvious equator (Fig. 2G). Taken together, these results demonstrate that the Fj and Ds expression gradients provide the directional cues that specify the orientation of PCP in the eye, but that the directional information provided by the two gradients is partially redundant. Furthermore, these data indicate that both gradients are required to provide the robust directional cues needed to achieve the perfect fidelity of polarization observed in wild-type eyes.
|
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Alterations in the Fj and Ds gradients can re-orient ommatidial polarity
In order to provide further evidence that the orientation of the Fj and Ds
expression gradients specified the axis of PCP in the eye, I tested whether
reversing the expression gradients would lead to corresponding reversals of
ommatidial polarity. For this purpose, the previously described Vg1-Gal4 and
Omb3-Gal4 drivers were used to express Ds and Fj
(Tang and Sun, 2002). The
Vg1-Gal4 driver is an insertion in the fj gene and drives expression
in a graded fashion that is high at the equator and low towards the poles. The
Omb3-Gal4 driver, located in the optimotor blind gene, expresses Gal4
strongly at the extreme poles of the eye and rapidly declines towards the
equator.
Ectopic expression of Fj using either the Vg1-Gal4 or the ubiquitous
TubP-Gal4 drivers had little effect on the pattern of ommatidial polarity
(Fig. 3A,B). In each case, only
occasional mis-specified ommatidia were seen. These results were expected as
neither driver reverses the wild-type Fj gradient. By contrast, expression of
Fj under the control of the Omb3-Gal4 driver had profound effects in both
wild-type and fj animals. When the resulting eyes were sectioned to
reveal the area near the dorsal pole, large-scale reversals of ommatidial
polarity were observed (Fig.
3C,D) (see also Strutt et al.,
2004). Importantly, these reversals were located in the region
where the expression of the Omb3-Gal4 driver declines rapidly. The contrast
between the effects of Vg1-Gal4- and TubP-Gal4-driven Fj expression, and
Omb3-Gal4-driven Fj expression, demonstrate that reversing the Fj expression
gradient, but not merely overexpressing Fj, can override the normal PCP cues
and specify a new orientation of polarity. Consequently, these data strongly
support the proposal that graded expression of Fj is a source of PCP
directional cues in wild-type eyes.
|
Gradients of Fat expression can also provide directional cues to orient PCP
The results presented above demonstrate that the establishment of graded Fj
and Ds expression represent an essential step in providing the directional
information that orients PCP in the eye. In our earlier work, we proposed that
these expression gradients then direct ommatidial polarity by producing a
subtle equatorial gradient in Ft activity. As a result of this Ft gradient,
the equatorial R3/R4 precursor cell within each ommatidium would have a
slightly higher level of Ft function than the adjacent polar precursor cell.
This consistent difference in Ft activity within each ommatidium was proposed
to bias the Fz competition to ensure that the equatorial precursor cell always
assumes the high Fz signaling state. An expectation of this model is that
strongly graded ectopic expression of Fat, which is normally expressed evenly
across the eye imaginal disc, might be capable of overriding the normal
directional signals and specifying a new orientation of polarization.
In order to test this prediction, a P-element transgene was created that
placed Ft expression under the control of UAS transcriptional regulatory
elements. This transgene was used in combination with the TubP-Gal4, Vg1-Gal4
and Omb3-Gal4 drivers to provide different patterns of Ft expression. As Ft
plays an essential role in the regulation of epithelial proliferation, the
Vg1-Gal4 or OmbGal4 drivers were used to provide additional expression rather
than replacing endogenous Ft function
(Bryant et al., 1988;
Mahoney et al., 1991
). This
resulted in overall gradients of expression. The altered gradients produced
are shown in Fig. 4A-C. It is
worth noting for these experiments that the Vg1-Gal4 driver is substantially
stronger than the Omb3-Gal4 driver (data not shown).
|
Unlike TubP-Gal4- or Vg1-Gal4-driven expression, expression of Ft using the Omb3-Gal4 driver consistently led to polarity reversals (Fig. 4G). In each of ten eyes examined, a small group of ommatidia (from 2-5) displayed reversed polarity. These reversed ommatidia were found in the region of the eye where Omb3-Gal4-driven Fj had its effects, and which corresponds to the region where there is a decline of the Omb3-Gal4-driven gradient. These results suggested that providing a pattern of Ft that is higher at the poles provides a directional PCP cue that can overcome the cues provided by the endogenous Fj and Ds expression gradients. However, this effect is weak. In order to more clearly demonstrate the ability of a Ft expression gradient to provide a directional PCP cue, the effect of the Omb3-Gal4-driven Ft was examined in the absence of Fj function, which weakens the opposing endogenous directional information. A marked strengthening of the polarity reversal phenotype was observed under these conditions, with large groups of ommatidia near the poles co-ordinately reversing their polarity (Fig. 4H). These results confirm that the creation of a gradient of Ft function through ectopic expression is capable of providing a directional signal, and support the idea that the normal polarization pattern results from a high equator/low polar gradient of Ft activity.
The Dachsous and Four-jointed gradients do not orient PCP polarity in the wing
Several lines of evidence have suggested that gradients of Fj and Ds
expression might also orient planar polarization in the Drosophila
wing. These include the expression of Fj and Ds in opposing patterns, as well
as the severe polarization defects observed in ds animals
(Fig. 5B,F)
(Adler et al., 1998;
Ma et al., 2003
;
Strutt and Strutt, 2002
;
Zeidler et al., 2000
). In
addition, fj and ds mutant clones often show non-autonomous
effects on the polarity of nearby cells in a manner reminiscent to the effects
seen near clones of cells mutant for genes whose products are known to
participate in PCP signaling (Adler et al.,
1998
; Zeidler et al.,
2000
). Finally, clones of ft mutant cells in the wing
display polarity defects consistent with the idea that the mutant cells are
unable to directly sense global directional PCP cues
(Ma et al., 2003
).
|
The conclusion that the Ds and Fj expression gradients do not play
essential roles in orienting PCP in the wing was also made in a recent report
(Matakatsu and Blair, 2004).
However, that report did not directly assay animals in which both gradients of
expression were absent. Instead, strong ubiquitous Ds overexpression was used
to in an attempt to overwhelm the endogenous Ds gradient in fj
animals. Using our UAS-Ds expression construct, such conditions conditions
(w1118; fjN7/dsUA071, fjd1;
TubP-Gal4/UAS-Ds) do not lead to a loss of organized PCP in the eye,
although the PCP fidelity rate is considerably reduced (85%). As a result, the
experiments presented here represent a more rigorous test of the role of the
graded expression of Fj and Ds during the establishment of PCP in the
wing.
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Discussion |
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In our proposed model, the consistent equatorial bias of Fz signaling
results from more effective Ft action in each equatorial R3/4 precursor cell
when compared with its adjacent polar counterpart. As this Ft difference
results from the action of the Fj and Ds gradients, a key question is how
these gradients could control the level of Ft function. Important insight into
this issue has come from studies of the wing that suggest that Ft and Ds form
a complex in which the localization of Ft on the surface of one cell is
promoted by binding to Ds on the surface of the neighboring cell
(Ma et al., 2003;
Matakatsu and Blair, 2004
;
Strutt and Strutt, 2002
). The
dependence of Ft plasma membrane localization on Ds may account for the
requirement for Ds function during planar polarization in the eye even when
sufficient directional cues are provided by the Fj expression gradient.
The existence of Ds:Ft intercellular dimers suggests several mechanisms by which Ds might regulate Ft. One simple possibility is that Ds merely controls the accumulation of Ft on the surface of the neighboring cell. Thus, the relatively higher level of Ds in the polar R3/R4 precursor, which results from the polar gradient of Ds expression, would lead to the accumulation of more Ft on the bordering surface of the equatorial cell. This would result in an asymmetry in Ft protein levels precisely along the border between the precursor cells where Fz/PCP competition occurs. Although no such gradient has been observed, it would certainly be very subtle and perhaps undetectable. A second possibility is that Ds binding to Ft regulates Ft activity rather than localization. A third possibility is that Ds could participate with Ft in binding to the extracellular domain of a downstream target.
Fj appears to play a more limited role than Ds during planar polarization
of the eye. Unlike Ds, which both contributes a directional signal through its
graded expression and plays an essential role in the interpretation of
directional cues, Fj appears only to participate in PCP establishment via the
directional information provided by its graded expression. This more limited
role can be seen in the observations that either the absence or the ubiquitous
expression of Fj yields equivalent phenotypes, and does not grossly disrupt
the pattern of polarization unless the Ds gradient has been replaced with
ubiquitous expression. How might graded Fj fulfill this role? One possibility,
proposed by Ma et al. (Ma et al.,
2003) and Strutt et al.
(Strutt et al., 2004
), is that
Fj may regulate the ability of Ft and Ds to productively interact with each
other. Thus, the higher expression of Fj in the equatorial cell of each
ommatidium leads to more Ft:Ds dimers being formed with Ft in the equatorial
cell than in the opposite orientation. As Fj appears to function in the Golgi,
this regulation may involve the direct modification of Ft or Ds
(Strutt et al., 2004
).
It is important to note that one aspect of the data reported here requires
reconsideration of a feature of our previous model
(Yang et al., 2002). In our
previous work, we proposed that Fj acts upstream of Ds, perhaps by modifying
the Ds activity gradient. This placement was based on genetic experiments
showing that strong differences in Fj activity between R3/R4 precursor cells
can direct ommatidial polarization only when Ds is present. The identification
of an essential gradient-independent function for Ds clearly complicates the
interpretation of these epistasis experiments. As a result, it is no longer
possible to infer whether the information provided by the Fj expression
gradient acts upstream of Ds to modify the information provided by the Ds
gradient. An equally plausible possibility is that Fj regulates the function
of the Ds:Ft complexes by modifying Ft rather than Ds function.
Does Fat regulate long-range signals?
The work presented here was designed to test specific predictions of the
model proposed in our earlier study. However, alternate roles for Ft function
have also been proposed (Fanto et al.,
2003; Rawls et al.,
2002
). In one model, Ft regulates the production of an
unidentified long-range signal that is secreted at the equator and that
directly controls eye polarity (Rawls et
al., 2002
). The existence of such an unidentified patterning
signal, often called Factor X, has been invoked frequently to explain the
`domineering nonautonomy' phenomenon seen in both the wing and the eye near
clones of cells lacking function of PCP genes such as Fz (reviewed by
Adler, 2002
). In the alternate
model, the role of Ft is to prevent production of this factor everywhere in
the eye except at the equator where Ft activity is proposed to be inhibited by
unspecified mechanisms, presumably involving Ds. An important distinction
between the two models relates to the predicted effects of graded Ft
expression. In our model, graded Ft activity provides the key PCP directional
cues, and thus ectopic Ft expression gradients are predicted to have the
potential to orient ommatidial polarity. In the alternate model, gradients of
Ft activity do not provide directional cues. Instead, it is the lack of Ft
activity in a sharp zone at the equator that leads to the production of the
unidentified patterning factor. As a result, this second model predicts that
subtle gradients of Ft expression should not orient polarity, especially in
the polar regions of the eye where Ft activity is proposed to be uninhibited.
Thus, the data presented in this report demonstrating the orienting ability of
Ft expression gradients presents a challenge to this alternate model. In
addition, the need for Factor X, whose putative existence has been a common
feature of PCP models in both the wing and eye, has been challenged recently
on both experimental and theoretical grounds
(Ma et al., 2003
) (J. Axelrod
and C. Tomlin, personal communication). These reports have suggested that
domineering nonautonomy results from the tendency of neighboring cells to
align their polarization rather than the existence of an additional polarizing
signal.
Conservation of planar polarity signaling
The key roles of Ft and the Fj and Ds expression gradients in the eye
naturally raised the question of whether similar mechanisms are used to
provide directional cues in other tissues, such as the wing. That such
conservation might exist was suggested by the existence of gradients of Fj and
Ds in the wing. Additionally, it has been demonstrated recently that ectopic
gradients of Ft and Ds expression in the wing can produce re-orientation of
polarity in the wing (Matakatsu and Blair,
2004). Given the redundant nature of the directional cues provided
by the Fj and Ds gradients in the eye, the most rigorous way to evaluate the
roles of the Ds and Fj expression gradients in the wing was to examine the
consequences of removing the directional information of both gradients
simultaneously. When this was done, the resulting wings displayed almost
completely normal polarity. Thus, the Ds and Fj expression gradients do not
play a major role in orienting PCP in most of the wing blade. One possibility
is that there are additional directional signals that act redundantly with the
Ds and Fj gradients. Another possibility is that these gradients exist for
reasons unrelated to PCP. For example, they may serve to regulate the function
of Ft as a regulator of cellular proliferation
(Bryant et al., 1988
). Possible
support for such a role comes from the observation that flies in which both
graded Fj and Ds expression has been replaced with ubiquitous expression
survive to adulthood at reduced frequencies, and often display defects in the
size and shape of their legs, wings and eyes (data not shown).
The dispensability of the Fj and Ds gradients of expression during the
polarization of the wing indicates that there must be currently unidentified
directional cues directing wing PCP. Despite their mysterious nature, it is
likely that their mode of action will involve the Ds:Ft complex. This
inference can be drawn from the observation that animals lacking Ds function,
or clones of cells lacking Ft or Ds activity, have substantial PCP defects in
the wing. Importantly, clones of ft mutant cells in the wing appear
not to read directional cues and instead align their polarity with that of
their neighbors (Ma et al.,
2003). Thus, whatever the nature of the unidentified signals, they
appear not to function effectively in the absence of Ds and Ft. As neither Ft
nor Ds is directly required for the Fz PCP signaling at cell-cell junctions,
the dependence of these unidentified signals on Ds and Ft suggests that they
may act by asymmetrically modifying the action of the Ds:Ft complexes at
cell-cell junctions engaged in PCP signaling. Thus, the elegant regulation of
polarity in the eye by graded Fj and Ds expression may represent only one of a
number of ways to modulate the action of Ft. Further analysis of the
mechanisms by which Ft and Ds regulate the pattern of Fz/PCP signaling will
undoubtedly aid in the identification of these unknown signals and their mode
of action.
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ACKNOWLEDGMENTS |
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Footnotes |
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Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/131/24/6175/DC1
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