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First published online 10 January 2007
doi: 10.1242/dev.02786
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Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, 701 West 168th St, HHSC 1120, New York, NY 10032, USA.
* Author for correspondence (e-mail: at41{at}columbia.edu)
Accepted 14 December 2006
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Drosophila, Eye, Sloppy-paired, Dorsoventral signaling
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The cell types at the interface not only define the
position from which the signal will be released, but they also carry the
molecular information that directs which type of signal will be expressed, and
the modes of response of the cells. Interfaces between different cell types
can be established by a number of mechanisms. In the fly wing, the
dorsal-ventral (D-V) boundary is established by a compartment mechanism,
whereby cells on either side of the border are clonally isolated from one
another: dorsal cells express the Apterous (Ap) transcription factor and share
a lineage ancestry isolated from the ventral cells that do not express Ap
(Blair et al., 1994;
Diaz-Benjumea and Cohen,
1993). Differential adhesion between the two cell types leads to
the formation of a long interface (the D-V border). Borders between distinct
cell types can be generated by non-compartment mechanisms. For example, in the
vertebrate neural tube, Sonic Hedgehog released from the ventral floorplate
diffuses dorsally to elicit the expression of an array of different
transcription factors, each expression domain depending on its distance from
the source (Jessell, 2000).
This first step establishes a relatively crude array of expression domains
with many cells expressing more than one transcription factor. The
transcription factors, however, are autoregulatory and mutually repressive,
and if a cell initially expresses two, the action of one will force the
extinction of the other. As with the compartment mechanism, the transcription
factors also provide a miscibility code, such that like-cells mix and
unlike-cells repel, and sharply defined interfaces are formed.
There is great variability in the types of signaling that can occur at
interfaces. A particularly important form is that regulated by Fringe (Fng), a
glycocyltransferase that modifies the receptor Notch (N) and thereby modulates
its ligand sensitivities (Bruckner et al.,
2000; Moloney et al.,
2000; Munro and Freeman,
2000). The N/Fng-mediated signaling was first described at the D-V
border of the fly wing (Klein and Arias,
1998; Panin et al.,
1997) and has since been described elsewhere in fly and vertebrate
patterning (Haines and Irvine,
2003; Irvine,
1999). Once a Fng+-Fng- border is
established, a dynamic interaction between N and its ligands leads to
high-level ligand expression and consequential upregulation of N activity.
A Fng+-Fng- boundary also forms at the D-V midline of
the fly eye and the resulting N signaling activates a number of genes needed
for growth and patterning of the eye (Cho
and Choi, 1998; Dominguez and
de Celis, 1998;
Papayannopoulos et al., 1998).
The D-V midlines of the eye and wing display a number of major differences.
First, the D-V domains of the eye do not appear to be generated by a
compartment mechanism as clones can violate the D-V midline
(Becker, 1957). Second, in the
wing, Fng is expressed dorsally (under Ap transcriptional control), but in the
eye it is expressed ventrally [repressed dorsally by Iroquois (Iro)
transcription factors] (Cho and Choi,
1998; Dominguez and de Celis,
1998; Irvine and Wieschaus,
1994; Papayannopoulos et al.,
1998). Thus, the eye and wing both use the Fng/N signaling
mechanism at the D-V midlines, but the mechanisms by which the interfaces are
established are different.
Sloppy-paired 1 and 2 (Slp1 and Slp2) are homologous Forkhead transcription
factors that have extensive and frequently redundant roles in embryonic
patterning (Grossniklaus et al.,
1992). We describe here the ventral-specific expression of Slp
proteins in the developing eye. We show that Slp and Iro proteins are mutually
repressive transcription factors expressed in the ventral and dorsal domains
of the developing eye, respectively. Initially, the two domains directly abut
at the center of the eye disc, but as development proceeds a gap opens up
between them. This gap is caused by the N-induced downregulation of
slp, which facilitates the upregulation of Serrate, one of the N
ligands.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), eyg-Gal4
(Wehrli and Tomlinson, 1998),
Tub>Gal80, y+>Gal4 (gift from Gary Struhl),
UAS-slp1 (gift from Gary Struhl), UAS-slp2
(Riechmann et al., 1997),
UAS-mirr (Cavodeassi et al.,
2000), UAS-Nintra
(Struhl and Adachi, 1998),
UAS-GFP (Bloomington Stock Center), iroDFM3
(Gomez-Skarmeta et al., 1996),
UAS-P35 (Hay et al., 1994),
Nts (Shellenbarger and
Mohler, 1978) and hs-N-GV
(Chung and Struhl, 2001).
Clones were made using slpS37A FRT40A,
ubi-GFP, FRT40A (Bloomington Stock Center), hs-GFP
M(2) w+30C FRT40A (gift from Gary Struhl),
iroDFM3 FRT2A
(Tomlinson, 2003) and
hs-GFP M(3)i55 FRT2A chromosomes (gift from Gary Struhl). We
also made slpS37A mutant clones with UAS-P35 using MARCM
methods (Lee and Luo, 1999).
Clones were induced at 48 or 72 hours before dissection.
Nts flies were grown at 18°C and shifted to 31°C
and left for 24 hours before dissection.
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Histology
Antibodies used were rat anti-Mirr
(Yang et al., 1999) (1:2000),
rat anti-Ser (Papayannopoulos et al.,
1998) (1:1000), mouse anti-Dl (DSHB, 1:600), rabbit anti-LacZ
(Cappel, 1:2000), mouse anti-ß-galactosidase (Promega, 1:500),
anti-rabbit IgG Alexa Fluor 488-conjugated (Molecular Probes, 1:1000),
anti-mouse IgG Alexa Fluor 488-conjugated (Molecular Probes, 1:1000),
anti-rabbit IgG Cy3-conjugated (Jackson, 1:1000), anti-mouse IgG
Cy3-conjugated (Jackson, 1:1000), anti-rat IgG Cy3-conjugated (Jackson,
1:1000), anti-mouse IgG Cy5-conjugated (Jackson, 1:500) and antidigoxigenin
alkaline phosphatase-conjugated (Roche, 1:2000). Standard methods were used
for antibody staining. slp1, slp2
(Grossniklaus et al., 1992),
mirr (McNeill et al.,
1997) and fng (Irvine
and Wieschaus, 1994) cDNAs were used for in situ hybridization
following Curtiss and Mlodzik (Curtiss and
Mlodzik, 2000) and/or Sato et al.
(Sato et al., 1999).
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eye discs were double-stained for transcriptional activity of the iro complex (dorsally expressed) and the slp complex (ventrally expressed) to determine the spatial relationship of the two expression domains. In second-instar eye discs, mirror (mirr, one of the three iro genes) transcription was exclusively dorsal (Fig. 1D,E) whereas slp was exclusively ventral (Fig. 1C,E), and the two expression domains directly abutted (with no overlap) in the medial region of the eye disc (Fig. 1E). In the third larval instar the morphogenetic furrow (MF) begins to progress across the presumptive retina, and slp and mirr transcription was extinguished in post-furrow regions as evidenced by in situ hybridization (not shown). However, lacZ reporters from both genes showed persistent expression posterior to the MF, which is likely to result from perdurance of the long-lived lacZ gene product (Fig. 1F). Ahead of the furrow mirr was still exclusively dorsal, and slp ventral, but now the two expression domains did not abut; instead, a gap opened that appeared to be generated by loss of slp expression in the region close to the D-V midline (white arrowhead in Fig. 1F).
Generation of a slp1, slp2 mutant
slp1 and slp2 are functionally redundantly elsewhere in
Drosophila development
(Grossniklaus et al., 1992),
and as transcripts from both genes were expressed identically in the
developing eye, both needed to be removed for an effective loss-of-function
analysis to be performed. The only existing lesion that removes both
transcripts (without affecting other loci) is on a CyO balancer
chromosome (Grossniklaus et al.,
1992; Grumbling and Strelets,
2006) that was not useful to us. We therefore generated a new
deficiency mutation (slpS37A) by mobilization of the
slpAvm insertion. Molecular characterization of
slpS37A showed a deletion that removes the slp1
transcription unit and all intervening sequence to 16 bp downstream of the
slp2 transcriptional start site
(Fig. 1B). Thus, although the
slp2 coding sequence is intact, the promoter sequence is removed. To
test whether the lesion is effectively null for both transcripts it was
crossed to a slp
34B deficiency
and a `null' embryonic phenotype of fused denticle belts was observed (not
shown) (Grossniklaus et al.,
1992).
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). Again,
these clones were similar to those induced in wild-type tissues, and thus the
under-representation of ventral slpS37A cells does not
appear to result from programmed cell death.
Slp and Iro are mutually repressive transcription factors
Since Slp and Iro are transcription factors expressed in abutting domains
of the second-instar disc (Fig.
1E), we examined the ability of one to regulate the expression of
the other. When slp1 was ectopically expressed in dorsal clonal
patches (marked by the coexpression of GFP), a correlating cell-autonomous
suppression of mirr transcription was observed
(Fig. 2A). Some of the
Slp-expressing cells showed residual mirr-lacZ expression
(inset in Fig. 2A''), but
this represented significantly reduced staining, suggesting that these cells
are in the process of extinguishing mirr expression. Furthermore, the
lacZ gene product has long perdurance. Thus, Slp appears to be an
effective suppressor of iro gene expression. When mutant clones for
all three genes of the iro gene complex (iroDFM3)
were induced in dorsal regions, slp transcription was coincidentally
upregulated (Fig. 2B). However,
slp was typically expressed in the center of such clones and not at
their peripheries (Fig. 2B).
This observation suggests: (1) that Iro expression normally functions to
repress dorsal expression of slp; and (2) that the creation of an
Iro+-Iro- interface generates an influence that locally
suppresses slp expression (the absence of slp expression at
the clone periphery).
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The sub-viability of ventral slp clones prevented an effective assessment of any role that Slp might play in suppression of ventral iro expression.
These above experiments indicate: (1) that Slp and Iro are mutually repressive transcription factors; (2) that Iro actively suppresses slp expression in the dorsal domain; and (3) that an Iro+-Iro- interface generates an slp-repressing influence, which we show below to be N activity.
The roles of Iro and Slp in regulating fng expression
Fng is expressed exclusively in ventral eye disc cells (red in
Fig. 3A-B), and at the D-V
midline a Fng+-Fng- interface is formed (arrowhead in
Fig. 3B). Hitherto, Iro has
been shown to repress fng transcription dorsally
(Cho and Choi, 1998;
Dominguez and de Celis, 1998;
Papayannopoulos et al., 1998).
However, when slp is ectopically expressed in dorsal cells, an
upregulation of fng transcription occurs (arrows in
Fig. 3C). Correspondingly, when
iro is clonally expressed ectopically in the ventral territory, a
downregulation of fng transcription occurs (arrow in
Fig. 3D). This raised the
question of whether Iro prevented dorsal fng expression indirectly,
by repressing slp expression. When slp and mirr
were co-expressed in clonal patches (both dorsally and ventrally), they
behaved as mirr alone; there was no dorsal fng upregulation
(arrow in Fig. 3E) and there
was repression of ventral fng expression (arrowhead in
Fig. 3E). Furthermore, we note
that surviving ventral slp mutant clones do not show phenotypes
typical of Fng+-Fng- interfaces (not shown), which would
have arisen if Slp activated ventral fng expression. Thus, it appears
that Slp does not promote the ventral expression of fng.
Notch activity suppresses slp expression
In second-instar eye discs, the Slp and Iro domains directly abut at the
midline of the disc (Fig. 1E),
and yet by the late third instar a gap opens between them
(Fig. 1F). Furthermore, in the
clonal experiments described above, whenever an
Iro+-Iro- interface was generated, a local
downregulation of slp transcription was observed
(Fig. 2B-C). Thus, wherever we
observed an Iro+-Iro- interface, whether at the normal
midline or in clonal experiments, there was a local downregulation of
slp expression. Since Iro+-Iro- interfaces
establish Fng+-Fng- interfaces (which lead to local N
activation), we wondered whether N was the slp-repressing signal.
When a constitutively activated form of the N protein
(Nintra) (Struhl et
al., 1993) was expressed in the ventral regions of the eye discs,
a corresponding downregulation of slp expression occurred
(Fig. 4A). Thus N activation
appears sufficient to repress slp expression, suggesting that the gap
that opens up between the Iro and Slp domains in the third-instar disc is
caused by the local N activation at the midline interface. If this were true,
then removal of N function should prevent the formation of the gap.
To test whether endogenous N gene function was required for the
downregulation of slp, Nts mutant
(Shellenbarger and Mohler,
1978) larvae were grown at the permissive temperature until early
third instar and then shifted to 31°C for 24 hours before dissection and
staining. Such discs showed a complete absence of slp repression, and
the Slp and Iro domains abutted along the length of the midline interface
(Fig. 4C). The disc shown in
Fig. 4C
(Nts/Y) was treated identically to the control shown in
Fig. 4B
(Nts/+), but has a more immature appearance because N also
functions in MF progression (Baonza and
Freeman, 2001).
These experiments show that ectopic N activity suppresses slp, and that loss of endogenous N activity prevents the normal downregulation of slp expression. Thus, we infer that N activity is the influence present at Iro+-Iro- interfaces that downregulates slp expression.
The regulation of Dl and Ser expression
In the eye, Iro+-Iro- interfaces generate
corresponding Fng+-Fng- interfaces, which regulate the
activity of the two N ligands Delta (Dl) and Serrate (Ser), leading to a local
upregulation of N activity. One of the outputs of the N signaling is a local
increase in the expression of its ligands, which thereby further strengthens
the N activity (de Celis and Bray,
1997).
In the second-instar eye disc, Dl was ubiquitously expressed (red in
Fig. 5A), whereas Ser was
expressed in the region of the D-V border (arrow in
Fig. 5A)
(Cho and Choi, 1998;
Dominguez and de Celis, 1998;
Papayannopoulos et al., 1998).
In the third larval instar, N ligand upregulation occurred in two positions -
one associated with the Iro+-Iro- interface, and the
other not. These will be described below.
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). It
was found that the Iro+-Iro- interface runs as a
straight line through the eye region, but as it moves into the region of the
presumptive head capsule it curves sharply dorsal
(Fig. 6B). Expression of Dl and
Ser was upregulated about this border. Dl appeared as a stripe in the dorsal
cells next to the midline, running as a straight line through the eye field
and curving dorsally with the interface (red in
Fig. 5C'). Ser expression
was found to be more complicated: in the region of the eye, it filled the gap
vacated by Slp expression (green in Fig.
6A-B), and as it entered the head capsule region it bifurcated
into two `spurs'; the stronger one following the dorsally curving
Iro+-Iro- interface, and the weaker one bending
ventrally (green in Fig. 5C-D
and Fig. 6A-B).
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).
Strong N activity was found in the region of the
Iro+-Iro- interface, both in the midline region of the
eye and in the dorsally curving part in the presumptive head capsule (arrows
in Fig. 5B,D). Additionally,
however, N activity was detected in the region corresponding to the ventral
spur of Ser expression (arrowhead in Fig.
5B,D). This expression is weaker than its dorsal counterpart, but
it was consistently observed. In addition, a weak upregulation of Dl
expression was often detected at this location (arrowhead in
Fig. 5C', D''). This
ventral spur of N signaling is distant from and, by inference, independent of
the Iro+-Iro- interface. However, an additional
Fng+-Fng- interface appears to be present in the ventral
anterior region of the eye disc (arrows in
Fig. 3B') which
corresponds to the position of the ventral spur of N activity. Thus, this
appears to be an Iroindependent Fng+-Fng- interface that
regulates N signaling in the extreme ventral anterior of the eye disc. We note
that the mirr-lacZ line used in our experiments
(mirrF7) is also a w+ enhancer trap
for mirr (McNeill et al.,
1997), and in the adult the pigment fills the dorsal eye stopping
at the equator represented by the D-V midline
(Tomlinson, 2003). Thus, the
Iro+-Iro- interface defines the midline of the eye, and
the ventral spur of N activity appears to play no role in this patterning.
Ser upregulation correlates with downregulation of slp expression
In second-instar larvae, Ser is expressed about the D-V midline in both
Slp- and Iro-expressing cells. Thus, Ser expression is not `generically'
suppressed by these transcription factors, However, Slp appears to play a role
in regulating the subsequent upregulation of Ser.
In the eye region, the Ser upregulation occurs in the gap left by the
receding slp expression. N expression engenders both these effects:
it upregulates Ser expression
(Papayannopoulos et al., 1998)
and downregulates slp expression. In the mid-third larval instar, a
`peninsula' of slp expression was seen to project from the main
ventral body of expression and follow the dorsally curving
Iro+-Iro- interface (on its anterior side) (red in
Fig. 6A). The ventral spur of
Ser upregulation cut through this peninsula, and here a clear and correlating
downregulation of slp expression was observed (arrow in
Fig. 6A').
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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slp mutant clones
slp clones in the dorsal region of the developing eye appear
normal and healthy which suggests that there is nothing intrinsically wrong
with slp mutant cells. Yet, when induced in the ventral
(Slp-expressing) domain, the clones are sub-viable (white arrowheads in
Fig. 1H-I). Furthermore, the
cells that survive are likely to carry perduring gene function, so we suspect
that fully mutant ventral slp cells do not survive (arrow in
Fig. 1G-H). Neither the use of
the Minute technique, nor the presence of the apoptotic inhibitor
P35, affected the survival of the clones. These results suggest that the
slp mutant cells do not suffer a simple growth disadvantage with
respect to their Slp-expressing neighbors, nor are they removed by apoptosis.
Surviving clones (white arrowheads in Fig.
1H) show smooth borders, which suggests that they are `immiscible'
with their Slp+ neighbors, and that some adhesion mechanism may be
responsible for the removal of the cells. However, we did not observe
extrusion of mutant tissue from the epithelium that would be expected if
`immiscibility' was responsible for the loss of the mutant cells.
The relationship between Slp and Iro
Slp and Iro are mutually repressive transcription factors: when one is
expressed in the domain of the other, it suppresses the other's expression. In
dorsal iro mutant clones, slp is transcriptionally activated
(Fig. 2B), indicating that Iro
acts to prevent dorsal expression of slp. The reciprocal experiment
of examining iro transcription in ventral slp clones was
confounded by our inability to generate effectively null slp clones.
However, ventral slp clones induced at all stages throughout larval
development showed no evidence of mirr-lacZ expression (not
shown). Furthermore, we note that the gap is made from ventral cells that
turned off slp expression, and that iro expression does not
subsequently turn on in those cells.
We can view the relationship between Slp and Iro in one of two ways. First, both proteins function in their respective domains to suppress the expression of the other, and technical problems have prevented us from detecting the ventral suppression of iro by Slp. It this were the case, then both would be likely to function to ensure the emergence of a sharp interface between the two domains, in the manner described in the Introduction for vertebrate neural tube cell fates. The second possibility is that Iro represses dorsal slp expression, but Slp does not repress ventral iro expression.
In this second model, what would be the function of Slp vis-à-vis
Iro? Since Iro suppresses slp
(Fig. 2B-C) then this suggests
that the `ground state' of the eye tissue is to express slp, and that
it is excluded from dorsal expression by Iro. Wingless (Wg) is required for
Iro expression (Heberlein et al.,
1998), and in the embryonic eye disc primordium slp is
expressed in the majority of the eye primordium, being excluded from the
dorsal extreme (not shown). wg is expressed in the dorsal region
(data not shown) and we speculate that Wg promotes dorsal Iro expression which
suppresses the dorsal expression of Slp. Ventral Slp may then function to
repress any ventral iro expression engendered by diffusing Wg
signaling. The mutual repression of the two transcription factors would then
lead to cells adopting either the Slp-/Iro+ or
Slp+/Iro- state. Immiscibility effects between the cells
would then lead to the formation of the long straight midline border, and in
this regard we note that the surviving slp mutant clones round up
when surrounded by Slp+ cells (arrowheads in
Fig. 1H).
Slp and the upregulation of Ser
We have described (in two different positions in the eye disc) that loss of
slp expression correlates with the upregulation of Ser. One position
at which this occurs is the gap that forms next to the
Iro+-Iro- interface. The other is in the ventral region
of the presumptive head capsule ahead of the eye field; here a spur of Ser
expression shows a corresponding loss/reduction in slp expression
(arrow in Fig. 6A'). Not
only does the reduction of slp expression correlate with Ser
upregulation, but also restoration of Slp to the region of the gap prevents
the high levels of Ser normally found there
(Fig. 6C). Thus, reduction in
slp levels appears necessary for the increase in Ser levels. We note
that slp transcription is monitored here using slp-lacZ, and
as lacZ has significant perdurance, the gap is probably larger than
that indicated, and any overlap between Ser and slp is likely to be
less than that suggested by the images.
In wing D-V patterning there is no known `equivalent' of Slp - that is, a transcription factor that initially abuts the D-V interface but is then pushed back by the action of N signaling. Thus, this role of Slp appears specific to the eye, and this raises the question of its function. One explanation is that it acts as a brake on the N signaling. A major difference between the eye and wing is that a wave of differentiation sweeps the eye, and the midline N signaling is required specifically ahead of the wave front (the MF). A delicate balance may be required between the amount of N signaling ahead of the MF, and the speed with which the MF progresses across the disc. Slp may provide that control. As a repressor of Ser upregulation, Slp could act as a delay mechanism - slowing the increase in Ser, and thereby slowing the increase in N activation.
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ACKNOWLEDGMENTS |
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