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First published online 16 August 2006
doi: 10.1242/dev.02524
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1 Department of Pathology, Department of Genetics and Development, College of
Physicians and Surgeons, Columbia University, 701 West 168th Street, Room
1120, New York, NY 10032, USA.
2 Center for Neurobiology and Behavior, Department of Genetics and Development,
College of Physicians and Surgeons, Columbia University, 701 West 168th
Street, Room 1120, New York, NY 10032, USA.
Author for correspondence (e-mail:
at41{at}columbia.edu)
Accepted 7 July 2006
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Wingless, Snail family transcription factors, Fly eye periphery
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). By this method, a spatially arrayed gradient can be
converted into a spatially arrayed sequence of different cell types. The
majority of experiments that have investigated gradient mechanisms have used
differential gene transcription to monitor the responses of the cells with
little regard to the final cellular states. Here, we examine the organization
of the peripheral retina of the fly where a graded signal directs the
formation of a spatially arrayed series of distinct morphologically
structures. This system thus affords us the opportunity to investigate the
process of gradient signaling from the establishment of the signal itself,
through the responses of the cells and leading finally to the morphogenetic
elaboration of the spatially arrayed structures.
The Drosophila compound eye is composed of 
800 subunit
ommatidia, each of which contains eight photoreceptors (R1-R8), four
lens-secreting cone cells and two primary (1°) pigment cells. A hexagonal
array of secondary (2°) and tertiary (3°) cells surround the
ommatidia, and mechanosensory bristle cells occupy alternate vertices of the
hexagonal array (Ready et al.,
1976). At the periphery of the eye lie a number of specializations
(Fig. 1A).
). ;
Wernet et al., 2003). ; Ready et al.,
1976; Tomlinson,
2003). A number of features of the patterning of the periphery have been described, all of which are controlled by Wg secreted from the circumscribing HC.
;
Wolff and Ready, 1991). The
outer ommatidia that die frequently do not contain a full complement of cells
(Lin et al., 2004) -
photoreceptors, cone cells or 1° pigment cells can be absent. The
presumptive 2°/3° pigment cells that surround these dying ommatidia
survive and contribute to the PR
(Tomlinson, 2003). ). The
exclusive dorsal expression of Iroquis (Iro) transcription factors allows the
most peripheral surviving ommatidia to turn on Hth and adopt the DRO fate
(Tomlinson, 2003;
Wernet et al., 2003). ).
In order to further understand the mechanism by which Wg signaling
specifies these peripheral cell fates, we looked for potential Wg target genes
by screening enhancer trap lines for differential expression patterns in the
eye periphery. Four Wg target genes were identified: three encoded
transcription factors of the Snail family; the fourth was notum (also
known as wingful) that encodes a member of the
/ß-hydrolase superfamily that regulates Wg signaling by modifying
Drosophila glypicans such as Dally (Division abnormally delayed) and
Dally-like (Gerlitz and Basler,
2002; Giraldez et al.,
2002; Han et al.,
2005; Kirkpatrick et al.,
2004; Kreuger et al.,
2004).
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), UAS-arm*
(Zecca et al., 1996),
Actin>y+>wg (Struhl and
Basler, 1993) and Notum-Gal4 (S168)
(Gerlitz and Basler, 2002),
wg-lacZ, UAS-wg and UAS-lacZ (Bloomington Stock Center). The
dsh[v26] and arr2 clones were induced
as previously described (Wehrli and
Tomlinson, 1998); the esgG66B FRT40 and
esgG66B sna1 FRT40 chromosomes were from Shigeo
Hayashi (Fuse et al., 1996);
the notum3 FRT80B chromosome was described previously
(Giraldez et al., 2002).
The enhancer trap screen
An enhancer trap screen was conducted in which flies containing mobilized
P-elements carrying Gal4 with a minimal hsp70 promoter were screened in a
w[-]; UAS-w[+] background for peripheral pigmentation in the adult
eyes. Inverse PCR using P-element primers was used to identify genomic
insertion sites.
Constructs
The two UAS-worniuRNAi transgenes were made from
PCR-generated fragments (nucleotides 842-1430 and 1701-2176 of the cDNA)
inserted in opposite orientations into a pUAST-RNAi intron vector
(Lee and Carthew, 2003).
Phenotypes were examined at 30°C.
Immunostaining
Standard immunostaining was performed. Primary antibodies: rat
anti-Escargot (1:250) was from Xiaohang Yang; mouse anti-Cut (1:100), mouse
anti-Wg (1:50), mouse anti-Armadillo (1:10) and Rat anti-Elav (1:100) were
from the University of Iowa Hybridoma Bank; mouse anti-Coracle (1:500) was
from Richard Fehon; mouse anti-Worniu antibody was from Cai et al.
(Cai et al., 2001); mouse
anti-Snail (1:500) was a gift from Pierre Chambon; rabbit anti-ßGal
(1:2000) was purchased from Cappel; Cy3- and Cy5-conjugated secondary
antibodies were from Jackson Immunochemicals (West Grove, PA).
Standard histology and X-Gal staining
Histological preparation of adult fly eye and X-Gal staining of pupal eye
discs were performed as described previously
(Tomlinson, 2003).
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Analysis
of the genomic sequences flanking the insertion sites showed that each
corresponded to a different member of the Snail gene complex
(Fig. 1F); Cir1 was inserted
500 bp upstream of worniu (wor)
(Tang and Sun, 2002); RR was
400 bp upstream of the escargot (esg) gene; SK was
6 kb downstream of snail (sna).
Characterization of the expression patterns of the Snail family protein in the eye periphery
sna, esg and wor are considered to be functionally
redundant members of the Drosophila Snail gene family that encode
zinc-finger transcription factors (Ashraf
et al., 1999; Boulay et al.,
1987; Whiteley et al.,
1992). To examine the expression profiles of the encoded proteins,
we performed immunostaining in larval and pupal eyes. Esg protein was not
detected in the larval eye disc (data not shown) and first appeared at 32
hours after puparium formation (APF) in the most peripheral regions of the eye
(Fig. 2A). At this stage, the
peripheral ommatidia destined to be removed by apoptosis were still present,
and Esg staining was found in the HC [Fig.
2D - we identify the HC at this stage by its expression of Hth
(Dominguez and Casares, 2005;
Kenyon et al., 2003)]; in the
early PR (the thin layer of pigment cells that circumscribes the retina at
this stage, Fig. 2A); in the
peripheral interommatidia pigment cells (these are the cells that will join
the PR after their ommatidia die, Fig.
2A); and in the cone cells of the peripheral ommatidia
(Fig. 2C). Staining was not
observed in the photoreceptors (Fig.
2A'') or the 1° pigment cells of the peripheral ommatidia
(data not shown). We were unable to detect either Wor or Sna protein with the
available antibodies but suspected that this was due to ineffective detection
of the proteins rather than to their absence from the tissues. As Cir1 is a
Gal4 insertion in the wor locus
(Fig. 1F), transcriptional
activity of the gene was monitored using UAS-lacZ. Here,
lacZ activity was found to correspond with the expression of Esg;
being absent form the larval eye disc, and turning on at a third of the way
through pupal life in the pattern described above for Esg
(Fig. 2B). There was no
transcriptional reporter present in SK (the sna transposon insertion;
Fig. 1F) with which pupal
transcription could be monitored. However, given that all three Snail family
gene insertions show the same expression pattern in the adults (which probably
results from perdurance of pupal transcripts), we infer that sna may
also show the same expression profile as esg and wor.
Characterization of peripheral Wg expression
Lin et al. documented that Wg signaling from the HC elicits Wg expression
itself (32 hours APF) in the ommatidia that are destined to die
(Lin et al., 2004). Our
analysis indicates that this secondary Wg expression is restricted to the cone
cells of these ommatidia, not the photoreceptors. We stained both
wg-lacZ and -Wg, and counterstained with markers for cone
cells and photoreceptors (Fig.
2E,F). Thus, at this stage Sna family proteins are co-expressed
with Wg in the HC and in the cone cells but are additionally expressed in the
2° and 3° pigment cells surrounding the peripheral ommatidia
(Fig. 2G).
Wg signaling regulates snail family gene expression
To determine whether Wg signaling induced the peripheral Snail family
expressions, Wg signaling was ectopically activated in the main body of the
retina and the effects were assayed in both adult and pupal eyes. The arrow in
Fig. 3A indicates the ectopic
expression of RR-esg in an adult eye in cells in which Wg was
ectopically expressed (SK-sna and Cir1-wor behaved
similarly). In pupal retinas, ectopic expression of Wg and constitutively
activated Armadillo (
Arm) (Zecca et
al., 1996) induced both ectopic Cir1-wor transcriptional
activity (Fig. 3B) and Esg
protein (Fig. 3C). The
Arm induces Esg expression non-autonomously
(Fig. 3C), which results from
concomitant ectopic Wg expression (data not shown). Thus, ectopic activation
of the Wg pathway in the main body of the eye induces the expressions that Wg
normally controls at the periphery - namely the induction of Snail family
genes and wg itself.
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).
Collectively, the results of manipulation of Wg signaling are consistent with
the notion that Wg signaling induces the peripheral expression of Snail family
and wg gene expressions.
Wg signaling and the regulation of peripheral ommatidial cell death
The expression of Wg and Snail family proteins in the border regions
prefigures the subsequent removal of the peripheral ommatidia. Earlier
analyses of the apoptosis of these peripheral ommatidia examined only the
death of the photoreceptors (Hay et al.,
1994; Lin et al.,
2004; Wolff and Ready,
1991). As the cone cells express Wg and Snail family genes in
these ommatidia, we examined the sequence of apoptosis and found that the cone
cells died first (at 36 hours APF), some four hours before the death of
the photoreceptors. To demonstrate that cone cell removal occurred by the
apoptotic mechanism described for the photoreceptor, peripheral H99
homozygous clones [mutant for the three pro-apoptotic genes - hid,
reaper and grim (White et
al., 1996; Wing et al.,
2002)] were induced, resulting in the survival of the peripheral
cone cells (Fig. 4B).
Furthermore, in clones mutant for dsh or arr, the peripheral
ommatidia survived as evidenced by ectopic peripheral persistence of
Cut-expressing cells (the cone cells; Fig.
4A), Elav-expressing cells (the photoreceptors;
Fig. 4D'', arrowhead in
Fig. 4D'), and
Bar-expressing cells (the 1° pigment cells;
Fig. 4E). As these ommatidia
did not die, they did not release their associated 2° and 3° pigment
cells to join the PR. As a consequence, the PR in the dsh or
arr clones was significantly reduced in relation to the neighboring
wild-type tissue in which the ommatidia died (arrowhead versus arrow in
Fig. 4D').
Snail family regulation of peripheral cell fates
When Wg is ectopically expressed at high levels in the main body of the
eye, it induces the death of the ommatidia leaving a small eye containing only
pigment cells (Fig. 4C)
(Tomlinson, 2003). When Esg
(Fig. 4C) and Sna (data not
shown) were similarly expressed, small pigmented eyes resulted. Thus,
overexpression of Esg and Sna phenocopy Wg overexpression in the eye,
suggesting that they mediate at least some of the Wg signaling that occurs at
the periphery.
The roles of the Sna group proteins in mediating the peripheral Wg signal
were now examined in loss-of-function clones. Here, the experiments were
compromised by redundancy of gene function in the Snail complex
(Ashraf et al., 1999;
Ashraf and Ip, 2001;
Cai et al., 2001). Examination
of peripheral esg clones in pupal discs showed only infrequent
effects on the peripheral structures. esg, sna double mutant clones
showed a modest increase in these effects, but not until we made triple mutant
clones [by simultaneously introducing two different wor RNAi
constructs (see Materials and methods) in the esg, sna clones] did
substantial effects occur; the survival of peripheral ommatidia
(Fig. 4F,G) and concomitant
reduction of the PR (Fig. 4H).
Although clear and robust effects occurred in the triple mutant clones, not
all clones showed these effects. This probably resulted from the incomplete
removal of wor gene function by the RNAi technique. No effects were
observed on aspects of Wg peripheral signaling other than peripheral
ommatidial death and PR formation. For example the expression of Hth in the
DRO precursors remained unaffected (Fig.
4I), as did the patterning of the bald ommatidia (data not
shown).
Expression and function of Notum at the retinal margin
Another enhancer trap line (JW) given to us by Jill Willdonger carried a
lacZ reporter that showed peripheral eye expression (not shown). This
was an insertion 250 bp upstream of the notum gene, that encodes
an /ß-hydrolase that functions in the wing to restrict Wg
diffusion by modifying heparin sulfate proteoglycans such as Dally and
Dally-like (Gerlitz and Basler,
2002; Giraldez et al.,
2002). Using a notum-Gal4 line-S168-Gal4
(Gerlitz and Basler, 2002),
expression from the locus was found to begin 32 hours APF in the HC, in
the pigment cells of the PR and the peripheral interommatidial pigment
lattice, and in the cone cells of the peripheral ommatidia
(Fig. 5A,B,F). This expression
was similar to that of Esg (See Fig.
2G), except that the Notum expression did not extend as far into
the interommatidial pigment cells (Fig.
5F).
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Expression and role of Escargot in late eye development
Following its peripheral expression at 32 hours APF, Esg becomes
expressed specifically in all the 2° and 3° interommatidial pigment
cells throughout the retina at 40 hours APF
(Fig. 6A).
Cir1-wor showed an identical expression (data not shown),
but we were unable to monitor Sna expression. Although clones of dsh
or arr remove peripheral Esg expression
(Fig. 3D,E), in the main body
of the retina Esg expression was unaffected
(Fig. 6B). Thus, the earlier
peripheral expression of the Snail group genes appears to be controlled by Wg,
whereas the later central expression is not.
The precursors of the 2° and 3° pigment cells are a disordered
group of retinal cells that lie between the developing ommatidia. An apoptotic
cell pruning mechanism converts the array into a precise hexagonal lattice by
36 hours APF (Cagan and Ready,
1989; Miller and Cagan,
1998), and by 44 hours APF, the previously relaxed apical
profiles of the 2° and 3° pigment cells become constrained into a
necklace-like array (Fu and Noll,
1997; Wolff and Ready,
1991). Expression of Esg (40 hours APF) occurred in all the
2° and 3° pigment cells after their apoptosis but before their apical
constriction.
In esg mutant clones, the 2° and 3° pigment cell lattice formed correctly, but the cells failed to undergo apical restriction (Fig. 6C). Rhodamine phalloidin staining of the clones revealed no obvious defects in the actin cytoskeleton or cellular morphology throughout the depth of the cells (data not shown). There was no increase in severity of this phenotype in esg, sna or esg, sna, UAS-worRNAI clones, suggesting that Esg is the sole effector of the maturation of the 2° and 3° cells. This contrasts with the organization of the periphery, where all three proteins of the Snail complex appear to function redundantly. esg and esg, sna clones were examined in adult eye and a dramatic loss of 2° and 3° pigment cells was observed (although some still survived), resulting in gaps between ommatidia (arrowheads in Fig. 6D). All the other retinal cells appeared unaffected, and thus Esg appears to be specifically required for the survival and/or maturation of the 2° and 3° pigment cells.
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) which
represses Snail expression by inhibiting the transcriptional activity of
NF
B on the Snail promoter (Bachelder
et al., 2005; Barbera et al.,
2004). In addition, GSK-3 can phosphorylate Snail at two consensus
motifs, one for protein degradation (site I) and the other for subcellular
localization (site II) (Zhou et al.,
2004). Thus, in mammalian systems, Wnt signaling regulates Snail
gene activity both at the level of the transcript and the protein.
Snail group protein expression and the apoptosis signal
The apoptotic removal of the most peripheral ring of developing ommatidia
releases the surviving surrounding pigment cells to join and thicken the PR.
Ectopic expression of Snail family proteins mimics the ommatidial death that
is engendered by Wg expression, and loss of these proteins prevents the normal
Wg-dependent removal of the peripheral ommatidia and consequently disrupts the
PR. The Snail family transcription factors thus appear to direct the death of
the peripheral ommatidia and development of the PR. However, within the
peripheral ommatidia these proteins are expressed only in the cone cells -
they are absent from the photoreceptors (R cells) and the 1° pigment
cells. They are also present in the pigment cells surrounding the ommatidia.
This expression profile raises a number of points.
Our finding that Snail transcription factors promote death in
Drosophila eye periphery is in contrast to their anti-apoptotic roles
in other systems. For example in C. elegans, the Snail-like CES-1
(cell death specification) protein blocks death of the NSM sister cells during
embryogenesis (Thellmann et al.,
2003). In vertebrates, Slug (Snail2) is aberrantly upregulated by
the E2F-HLF oncoprotein in some leukemias, leading to increased cell survival
(Inoue et al., 2002;
Inukai et al., 1999).
Mammalian Snail has also been shown to confer resistance to cell death induced
by the withdrawal of survival factors in cell cultures
(Vega et al., 2004). However,
in the fly eye we describe a non-autonomous effect of Snail transcription
family members in apoptosis, which suggests that a different molecular pathway
is regulated from those of the autonomous examples above.
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) and it
supplies cells for the PR that optically insulate the entire eye
(Tomlinson, 2003). With regard
to the PR, there are two sources of cells. First there is the thin layer of
pigment cells that circumscribes the entire pupal eye and second there are the
later cells, originally associated with the moribund ommatidia, that
eventually incorporate into the existing PR to thicken it. Both aspects of PR
formation appear to be under Wg signaling control. During the larval phase,
the Hedgehog (Hh) morphogenetic wave sweeps the presumptive retina, triggering
the ommatidial differentiation process
(Heberlein et al., 1993;
Ma et al., 1993). However, Wg
is expressed in the flanking HC which inhibits the inductive mechanism
(Treisman and Rubin, 1995).
Thus, the larval retinal tissue directly adjacent to the HC does not undergo
ommatidial differentiation (Fig.
7A). The 2° and 3° pigment cell fate appears to be the
ground state of the retinal tissue
(Campos-Ortega and Gateff,
1976), and thus the cells directly adjacent to the HC are destined
to the pigment cell fate. Later in the pupa, Wg signaling triggers the death
of the peripheral ommatidia and releases their pigment cells to join the PR
and increase its thickness (Fig.
7B).
The co-expression of Wg and Notum in the peripheral cone cells
The expression of both Wg and Notum (its antagonist) by the cone cells of
the peripheral ommatidia is interesting. It may suggest that high levels of Wg
expression are required in the peripheral cone cells, but that the diffusion
of this cone-cell derived Wg needs to be tightly contained. For example, in
the model above where the death signal is provided by the peripheral cone
cells, high levels of Wg may be needed to trigger sufficient levels of the
apoptotic signal but any diffusion of the high levels of Wg would disturb
other aspects of the peripheral patterning.
In the absence of Notum, the effects of Wg signaling spread approximately
one more ommatidial row into the eye periphery. This relatively mild phenotype
suggests that there could be redundant mechanisms restricting the movement of
Wg gradient at the eye margin. In Drosophila wing disc, the Wg
receptor Drosophila Frizzled2 (Fz2) stabilizes Wg and allows it to
reach cells far from its site of synthesis. Wg signaling represses Fz2
expression, creating a gradient of decreasing Wg stability towards the D/V
boundary (Cadigan et al.,
1998). This might also be the case in the eye periphery, where Wg
signaling, in addition to activating Notum, might also represses Fz2 to limit
the extent of Wg diffusion.
Escargot regulates the maturation of 2° and 3° pigment cells in the main retina
Snail family gene expression in the 2° and 3° pigment cells appears
to be under two different control mechanisms; in the peripheral regions it is
activated by Wg signaling, but in the main body of the eye it is not.
Furthermore, the genes of the Snail complex appear functionally redundant in
the periphery but not in the main body of the eye. Here, the phenotypes of
esg clones are as strong as those of the mutations in all three
genes. This may be explained by differential regulation of the gene promoters
in the two positions. For example, in the main body of the eye, Esg expression
in the 2° and 3° pigment cells may activate expression of the two
other genes, but in the periphery, Wg signaling directly activates each of the
genes, with no cross-regulation between them. The majority of studies on the
specification of the main body 2° and 3° pigment cells have focused on
the mechanism of weeding out the surplus interommatidial cells which occurs
between 18 hours and 36 hours APF (Bao and
Cagan, 2005), but little is known about their subsequent
maturation. Our data showed that Esg is expressed in the interommatidial
pigment cells after the cell pruning mechanism, but before any sign of
morphological differentiation. In the esg mutants, the 2° and
3° pigment cells do not undergo correct apical constriction, indicating
that these cells are either developmentally delayed compared with their
wild-type counterparts or are blocked in their maturation. If the cells are
simply developmentally delayed, they should mature over time, but esg
mutant clones in the adult eye show degenerate or lost 2° and 3°
pigment cells (Fig. 6D). Thus,
Esg appears required for the appropriate maturation/survival of the 2° and
3° pigment cells. What happens to the esg mutant pigment cells
after the point when they fail to undergo apical restriction (whether they
delaminate or die/degenerate in place) remains to be investigated.
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ACKNOWLEDGMENTS |
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Footnotes |
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