1 Program in Developmental Biology, Baylor College of Medicine, One Baylor
Plaza, Houston, TX 77030, USA
2 Department of Molecular and Human Genetics, Baylor College of Medicine, One
Baylor Plaza, Houston, TX 77030, USA
3 Department of Pathology, Baylor College of Medicine, One Baylor Plaza,
Houston, TX 77030, USA
4 Biomedical Initiatives, University-wide AIDS Research Program, University of
California Office of the President, 300 Lakeside Drive, 6th Floor, Oakland, CA
94612, USA
5 Department of Anatomy, University of California San Francisco, Box 0452, 513
Parnassus, San Francisco, CA 94143-0452, USA
6 Department of Ophthalmology, Baylor College of Medicine, One Baylor Plaza,
Houston, TX 77030, USA
7 Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza,
Houston, TX 77030, USA
* Author for correspondence (e-mail: gmardon{at}bcm.tmc.edu)
Accepted 27 March 2003
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SUMMARY |
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Key words: eyes absent, hedgehog, Drosophila, Retinal determination, cubitus interruptus, Photoreceptor, Morphogenetic furrow
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INTRODUCTION |
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The adult Drosophila eye contains between 750 and 800 ommatidia
organized in a precise hexagonal array. Eight photoreceptors and 12 accessory
cells, including four cone cells, six pigment cells and one mechanosensory
bristle, comprise each ommatidium (Wolff
and Ready, 1993). The adult eye develops from an epithelial
monolayer called the eye imaginal disc, which is derived from a few cells set
aside during late embryogenesis
(Garcia-Bellido and Merriam,
1969
). Photoreceptor differentiation is initiated in early third
instar larvae at the posterior margin of the eye disc and proceeds anteriorly
following a synchronous wave of cellular changes termed the morphogenetic
furrow (MF) (Ready et al.,
1976
). Alterations in cell shape, cell cycle and patterns of gene
expression occur within the MF, and these changes ultimately generate
differentiated photoreceptors that are left in its wake
(Wolff and Ready, 1991
).
Therefore, a crucial event during Drosophila eye development is the
initiation of the MF.
Many lines of evidence suggest that hh signaling is required for
the initiation of the morphogenetic furrow. First, hh is expressed at
the posterior margin of the eye imaginal disc prior to photoreceptor
differentiation and in all cells posterior to the MF during its progression
(Borod and Heberlein, 1998).
Second, loss of hh function blocks initiation of the MF and impedes
its progression (Borod and Heberlein,
1998
). Third, posterior margin clones of a null allele of
smoothened (smo), the cell-autonomous receptor of
hh signaling, lack differentiated photoreceptors
(Curtiss and Mlodzik, 2000
;
Greenwood and Struhl, 1999
).
Fourth, loss-of-function clones of protein kinase A (pka),
an intracellular negative regulator of hh signaling, result in
ectopic activation of the hh signaling pathway and precocious
photoreceptor differentiation (Chanut and
Heberlein, 1995
; Dominguez,
1999
; Pan and Rubin,
1995
; Strutt et al.,
1995
). Similarly, several studies indicate that loss of
dpp signaling in the eye imaginal disc also blocks initiation of
photoreceptor differentiation. First, dpp is also expressed in the
posterior margin of the eye disc prior to initiation of photoreceptor
differentiation (Borod and Heberlein,
1998
; Chanut and Heberlein,
1997b
). Second, loss-of-function posterior margin clones of
mothers against decapentaplegic (mad), a nuclear effector of
dpp signaling, lack photoreceptor differentiation
(Wiersdorff et al., 1996
).
Third, the MF fails to initiate from ventral regions of eye discs from flies
that mutant for a hypomorphic allele of dpp
(Chanut and Heberlein, 1997a
;
Chanut and Heberlein, 1997b
;
Treisman and Rubin, 1995
).
Finally, ectopic expression of dpp leads to ectopic induction of the
MF from the anterior margin of the eye imaginal disc
(Chanut and Heberlein, 1997b
;
Pignoni et al., 1997a
). These
phenotypic similarities, coupled with the requirement for hh to
activate and maintain dpp expression
(Borod and Heberlein, 1998
;
Burke and Basler, 1996
),
suggest that dpp may be the sole target of hh signaling
during Drosophila eye development.
Using a combination of loss- and gain-of-function genetics, we demonstrate
that the major role of Hh signaling during Drosophila eye development
is to alleviate the repression of dpp and eya by
Cirep. Additionally, loss-of-function analyses suggest that the
full length, activated Ciact plays little or no role in
Drosophila eye development. Based on these results, we conclude that
eya is the critical tissue-specific target of Hh signaling during the
initiation of normal photoreceptor differentiation in Drosophila.
Furthermore, our results suggest that Hh does not function as a classical
morphogen during the initiation of retinal morphogenesis
(Freeman and Gurdon, 2002).
Instead, we propose that Hh signaling acts as a binary switch to initiate
photoreceptor differentiation during Drosophila eye development.
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MATERIALS AND METHODS |
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Clonal analysis
To induce large clones of smod16-/- in the
eye, we used the FLP-mediated mitotic recombination system in a Minute
background (Xu and Rubin,
1993). Mutant clones from such discs are marked by the lack of a
ß-galactosidase reporter. To reintroduce single gene or multigene
combinations into smod16-/- clones, a variation
of the MARCM technique was employed (Lee
and Luo, 1999
). Generally, y w hs-FLP; smod16
FRT40A/CyO; UAS-gene(s)/TM6B, Tb females were crossed to w;
M(2)24F arm-lacZ tub-GAL80 FRT40A/Bc Elp; ey-GAL4 males. Half the
non-Bc, non-Tb larvae contained negatively marked (lack of
ß-galactosidase expression) clones. Additionally, within these clones,
GAL4 repression by GAL80 is lost and the transgene(s) of interest is
expressed. A minimum of 10 eye discs containing large smo clones were
analyzed for each genotype and yielded consistent results.
Larvae containing marked ci mutant clones were generated as
described previously (Methot and Basler,
1999). In order to induce large mutant clones, we recombined the
M(2)531 mutation onto the ci genomic rescue
chromosome described previously (Methot
and Basler, 1999
). Additionally, we recombined an
arm-lacZ transgene onto the same genomic rescue chromosome to
unambiguously mark mutant cells in both larval discs and adult sections. The
genotype of the animals is: y w hs-FLP; FRT42 P{ci1} hsp70-GFP arm-lacZ
M(2)531/FRT42; ci94/ci94.
Adult animals containing clones were identified by the yellow mutant
phenotype, the mosaic eye color and the presence of wing phenotypes. Adult
eyes were fixed, embedded and sectioned as described previously
(Tomlinson and Ready,
1987).
Immunohistochemistry
The following primary antibodies were used in this study: rat anti-Elav
(1:600), rabbit anti-ß-galactosidase (1:1000; Cappel), mouse Anti-Eya,
10H6 (1:200), guinea pig Anti-Senseless (1:800)
(Frankfort et al., 2001).
Conjugated goat anti-mouse, rat, rabbit and guinea pig fluorescent secondary
antibodies were ALEXA 488 (Molecular Probes), Cy3 (Jackson Immunochemicals) or
Cy5 (Jackson Immunochemicals), all at 1:600 dilution. HRP-conjugated goat
anti-mouse antibodies were used as previously described
(Chen et al., 1999
). Discs
were then processed as described previously
(Frankfort et al., 2001
).
Fluorescent images were captured with a Zeiss LSM 510 confocal microscope. All
other images were captured on a Zeiss Axioplan microscope with Nomarski
optics. All images were processed with Adobe Photoshop software.
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RESULTS |
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We hypothesized that the inability of ey and dpp misexpression to activate photoreceptor differentiation in the anterior compartment of the wing disc is due to the repression of Hh target genes by Cirep. In the posterior compartment, however, the absence of Cirep allows ey- and dpp-mediated retinal differentiation. This model predicts that misexpression of ey and hh together in the 30A-GAL4 pattern would prevent production of Cirep and induce photoreceptor differentiation, but only in the anterior compartment. Indeed, ey and hh misexpression induces robust Eya expression and photoreceptor differentiation specifically in the anterior compartment (Fig. 1B,E). In addition, we find that misexpression of ey, dpp and hh together with the 30A-GAL4 driver leads to Eya activation and photoreceptor differentiation in both compartments of the wing disc (Fig. 1C,F). These results demonstrate that dpp alone cannot bypass the requirement for Hh signaling to induce Eya expression during ey-mediated ectopic photoreceptor differentiation in the anterior compartment of the wing disc. The induction of robust Eya expression in the anterior compartment of the wing disc upon co-expression of ey and hh led us to hypothesize that eya is normally repressed by Cirep. Furthermore, this hypothesis predicts that expression of ey, dpp and eya together should bypass the requirement for Hh signaling and induce photoreceptors in both compartments of the wing disc.
eya and dpp can bypass the requirement for Hh
signaling in the wing disc
30A-GAL4 driven expression of dpp, ey and eya
can induce Dac expression and photoreceptor differentiation in both
compartments of the wing disc (Fig.
2A,D). This effect becomes more penetrant when dpp, ey,
eya and so are co-expressed
(Fig. 2B,E). However, the
effects of dpp, ey, eya and so misexpression are not due to
induction of hh because a hhlacZ reporter
(hhP30) is not activated in the anterior compartment
(Fig. 2G-I). Finally,
expression of ey, hh, eya and so can induce Dac expression
and photoreceptor differentiation only in the anterior compartment of the wing
disc, confirming that dpp is essential in this process
(Fig. 2C,F). Thus, eya
and dpp together are sufficient to bypass the requirement for Hh
signaling in the wing disc. Moreover, these results suggest that in addition
to dpp, hh is also required for eya expression during normal
retinal development, most probably by blocking Cirep. Two models
are consistent with the ability of dpp and ey to induce
photoreceptor differentiation in the posterior compartment of the wing disc
where Hh signaling is not normally active. First, co-expression of
dpp and ey may lead to the misexpression of ci in
the posterior compartment of the wing disc, thereby allowing Hh signaling to
occur. This appears unlikely because no Ci induction is detected in the
posterior compartment in response to ey and dpp expression
(data not shown). We favor an alternate model in which ey and
dpp together may be sufficient to induce Eya expression and
photoreceptor differentiation in the posterior compartment of the wing disc in
the absence of Cirep. If true, this model predicts that loss of
ci function in the eye should have no effect on Eya expression and
photoreceptor differentiation.
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Restoration of either dpp or eya expression alone in
posterior margin smo clones does not rescue photoreceptor
differentiation within the clone (Fig.
5A,C). Similarly, delayed progression of the MF in interior
smo clones is not rescued by the expression of dpp or
eya alone (Fig. 5B,D).
Furthermore, co-expression of eya and so also does not
rescue either initiation or progression of photoreceptor differentiation
within smo clones (data not shown). By contrast, expression of
dpp and eya together restores photoreceptor differentiation
in posterior margin smo clones with complete penetrance
(Fig.5E). Similarly, furrow
progression through internal smo clones expressing both dpp
and eya is normal (Fig.
5F). Anterior margin smo clones expressing both
dpp and eya also differentiate clusters of photoreceptors
but with incomplete penetrance (data not shown). These results demonstrate
that dpp is not the sole target of Hh signaling in the eye and that
eya is the crucial tissue-specific Hh target during retinal
morphogenesis. Our analysis in the wing disc suggests that overexpression of a
combination of ey, dpp, eya and so is most effective in
bypassing the requirement for Hh signaling during ectopic photoreceptor
differentiation (Fig. 2C). We
tested whether co-expression of dpp, eya and so in
smo clones was also more effective in inducing photoreceptor
differentiation. Although posterior margin smo clones are rescued
with similar efficiency as the combination of dpp and eya,
ectopic anterior furrows are induced with high frequency when dpp,
eya and so are expressed in smo clones
(Fig. 5E-H). This result is
consistent with the synergistic effects of eya and so
co-expression during ectopic photoreceptor differentiation
(Pignoni et al., 1997a).
Finally, expression of dpp and so in smo mutant
clones does not rescue photoreceptor differentiation, further demonstrating
that eya is the specific downstream target of Hh signaling during the
initiation of the MF (data not shown).
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DISCUSSION |
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ey, dpp and eya can bypass the requirement
for Hh signaling to initiate ectopic retinal morphogenesis
Misexpression of ey in the wing disc causes ectopic photoreceptor
differentiation only in regions where both dpp and hh
signaling are normally active. The simplest explanation for this effect
invokes a linear regulatory hierarchy where hh induces dpp,
which in turn cooperates with ey to initiate retinal morphogenesis.
While, misexpression of ey and dpp together does indeed lead
to synergistic photoreceptor differentiation, this occurs only in the
posterior compartment of the wing disc. Notably, Hh signaling is not
transduced in the posterior compartment of the wing disc due to the repression
of ci by En (Alexandre et al.,
1996). Furthermore, dpp and ey expression does
not induce Ci expression in the posterior compartment of the wing disc. Thus,
we conclude that dpp and ey can induce Eya expression and
photoreceptor differentiation in the posterior compartment of the wing disc in
the absence of Hh signaling and Cirep. Misexpression of hh
and ey induces robust eya expression and photoreceptor
differentiation in the wing disc, but only in the anterior compartment. This
result is consistent with a model in which Hh signaling normally blocks the
production of Cirep and converts it into an activated form,
Ciact, in the anterior compartment of the wing disc.
Ciact can induce dpp expression in the anterior
compartment (Alexandre et al.,
1996
) and dpp can in turn cooperate with ey to
induce robust Eya expression and photoreceptor differentiation. Consistent
with this model, co-expression of hh, dpp and ey leads to
Eya expression and photoreceptor differentiation in both compartments of the
wing disc. Taken together, these results suggest that, in the wing disc,
ey and dpp can activate eya expression only in
absence of Cirep.
Co-expression of dpp, ey and eya using the 30A-Gal4 driver induces photoreceptor differentiation in both wing compartments, albeit with low penetrance. This effect becomes stronger and more penetrant when dpp, ey, eya and so are misexpressed in a ring around the wing pouch. These results demonstrate that providing ey, dpp and eya from an exogenous source is sufficient to bypass the requirement for Hh signaling during initiation of ectopic photoreceptor differentiation. In addition, these results implicate eya as a key target for Hh signaling during the initiation of normal retinal morphogenesis, most likely by blocking Cirep.
The adult Drosophila eye develops normally in the absence of
ci
The data from our ectopic expression analyses in the wing disc suggest that
Cirep has a major role in blocking eya expression in areas
that are not exposed to Hh signaling. However, Ciact also plays an
important role in patterning the anterior compartment of the wing disc
(Methot and Basler, 1999). For
example, adult wings that contain ci mutant clones develop with
defects in the anterior compartment
(Methot and Basler, 1999
)
(this paper). In the Drosophila eye disc, ci is expressed
uniformly but Ci protein expression follows a dynamic pattern. It has been
proposed that in regions anterior to the furrow Ci is subject to PKA-dependent
phosphorylation and SCFSlimb-dependent processing into
Cirep (Ou et al.,
2002
). Cells in the MF, however, receive and transduce the Hh
signal and prevent the proteolytic processing of Ci, therefore blocking
production of Cirep. Furthermore, it has been proposed that cells
that are posterior to the MF do not accumulate Cirep in a
PKA-dependent manner. Instead, these cells use a smo- and
cullin3- dependent proteolytic process leading to the complete
degradation of Ci (Ou et al.,
2002
). Therefore, the role for Ci in the eye appears to be limited
only to cells that are part of, and anterior to, the MF. However, these
studies do not establish separate functional roles for Ciact and
Cirep in the developing eye.
Surprisingly, Eya expression and photoreceptor differentiation are not perturbed in Drosophila eye discs that contain large ci-null mutant clones. Similarly, adult eyes containing large ci mutant clones appear normal both externally (data not shown) and in internal sections. These results, coupled with our ectopic expression analysis in the wing disc, suggest that Ciact plays little or no role during normal photoreceptor differentiation. Furthermore, these results support a model in which the major role for Hh signaling during the initiation of photoreceptor differentiation is to prevent the production of Cirep.
Interestingly, ci-null mutant clones that span the furrow do not
hasten furrow progression. Although ectopic activation of the Hh pathway is
sufficient to induce precocious furrow advancement and photoreceptor
differentiation (Heberlein et al.,
1993; Pan and Rubin,
1995
; Strutt et al.,
1995
), loss of Ci is not. A likely explanation for this apparent
contradiction may be found in the distinction between loss- and
gain-of-function experiments. Specifically, although Ciact normally
plays little or no role in eye development, ectopic production of
Ciact is sufficient to induce precocious furrow advancement.
Intriguingly, vertebrate homologs of Drosophila ci have evolved to
carry out either activator (Gli1 and Gli2) or repressor
(Gli3 and perhaps Gli2) functions independently
(Ingham and McMahon, 2001
).
Our findings demonstrate that in the absence of gene duplication,
tissue-specific separation of these functions has also occurred in
Drosophila.
Threshold effects of Hh signaling during Drosophila eye
development
We propose that Hh signaling acts as a binary switch during
Drosophila eye development to control the timing of initiation of
photoreceptor differentiation. Specifically, our data suggest that during
early larval development Cirep normally inhibits retinal
morphogenesis by blocking eya and dpp expression. Hh
signaling in late second instar larvae blocks production of Cirep,
which in turn allows dpp and eya expression, MF initiation,
progression and photoreceptor differentiation. Rather than regulating the
differentiation of multiple cell types in a concentration-dependent manner,
our data suggest that Hh signaling acts as a molecular switch that is
sufficient to initiate dpp and eya expression and retinal
morphogenesis. This model also explains the seemingly contradictory phenotypes
of loss of smo (blocks MF initiation) and loss of ci (no
effect) during Drosophila eye development. Loss of ci
creates a permissive environment for eya and dpp expression
and photoreceptor differentiation, rendering eye development Hh independent.
By contrast, Cirep persists in the absence of smo function
and thus photoreceptor morphogenesis does not occur in smo clones. As
ci null mutant clones in the eye develop normally, other
Hhindependent mechanisms must also act to control the initiation of retinal
morphogenesis in Drosophila.
Recent studies analyzing the role of the Hh signaling pathway in organizing
dorsoventral pattern in the developing vertebrate neural tube present a useful
comparison with the developing Drosophila eye. Specifically, Gli3, a
homolog of Drosophila Ci, acts as a transcriptional repressor in
patterning the intermediate region of the developing spinal cord
(Persson et al., 2002). Normal
patterning of the ventral spinal cord requires the establishment of a gradient
of Hh signaling (strongest ventrally), which acts in part by preventing the
repressive activity of Gli3 (Wijgerde et
al., 2002
). Furthermore, this gradient specifies multiple,
distinct cell fates, depending on the distance from the source of Hh
(Ingham and McMahon, 2001
). In
the absence of Hh signaling, Gli3 repression expands ventrally and
inappropriately blocks certain ventral spinal cord cell fates
(Wijgerde et al., 2002
).
Moreover, in Smo Gli3 double mutant mice, these ventral cell fates
are restored. These results suggest that blocking production of the Gli3
repressor is a key step in spinal cord development and closely parallels work
presented in this study. However, in contrast to the Drosophila eye
(where Hh acts as a binary switch), the actions of Hh signaling during the
patterning of the vertebrate spinal cord are concentration dependent.
Co-expression of dpp and eya can rescue
smo mutant clones
Posterior margin smo mutant clones lack Eya expression and
photoreceptor differentiation (Curtiss and
Mlodzik, 2000) (this paper). We attribute the lack of eya
expression in these cells to their inability to block the production of
Cirep. Furthermore, our data demonstrates that co-expression of
dpp and eya in these posterior smo mutant clones
rescues photoreceptor differentiation. In addition, dpp and
eya co-expression is sufficient to rescue delayed furrow progression
in smo clones. However, the precise temporal and spatial order of
photoreceptor recruitment may not be rescued in these clones. Thus, the
requirement for Hh signaling in the eye can be circumvented by the expression
of the downstream targets dpp and eya. These results
demonstrate that eya is a crucial eye-specific target of Hh signaling
during the initiation of retinal differentiation and has led to a new model
for the initiation of retinal morphogenesis
(Fig. 6). In this model, Hh
signaling blocks the proteolytic degradation of Ciact into
Cirep, thus allowing initiation of dpp expression. Once
dpp expression is established, the absence of Cirep allows
dpp to act in parallel with ey to initiate eya
expression, which in turn leads to so expression. Furthermore,
dpp cooperates with eya and so to initiate the
expression of dac and extensive feedback regulation among these genes
leads to consolidation of retinal cell fates.
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ACKNOWLEDGMENTS |
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