Department of Cell Biology, Emory University School of Medicine, 1648 Pierce Drive, Atlanta, GA 30322-3030, USA
*Author for correspondence (e-mail: kmoses{at}cellbio.emory.edu)
Accepted April 23, 2001
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SUMMARY |
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Key words: Egfr, Notch, Wingless, Hedgehog, Dpp, Morphogenetic furrow, Drosophila
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INTRODUCTION |
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It has been shown that ectopic Ras pathway signaling can induce ectopic photoreceptor development anterior to the furrow (Dominguez et al., 1998). We now show that Epidermal Growth Factor Receptor (Egfr) and Notch signaling act cooperatively and are necessary and sufficient for the initiation of the endogenous morphogenetic furrow: removal of either signaling pathway results in a block in furrow initiation, while ectopic expression along the margins ahead of the furrow leads to ectopic retinal differentiation. The initiation of the furrow at the posterior margin and its re-initiation along the lateral margins has been thought to be a single process. We show that these two events are temporally and genetically separable, and now refer to the initiation of the furrow at the intersection of the posterior margin and midline as birth and the continued re-initiation along the lateral margins as reincarnation.
The Egfr is a transmembrane receptor tyrosine kinase (RTK) that acts through the Ras cascade (Nilson and Schüpbach, 1999; Schweitzer and Shilo, 1997). In the developing eye, Egfr signaling has been shown to control cell fate specification, inhibit programmed cell death and modulate cell cycle progression (Bergmann et al., 1998; Freeman, 1998; Kumar and Moses, 2000; Kurada and White, 1998). Notch is a transmembrane receptor activated by DSL class ligands and transduces signals to the nucleus by means of a pathway that includes the Enhancer of Split Complex genes (E(spl)C; Artavanis-Tsakonas et al., 1995). During eye development, Notch is involved in setting up the dorsal-ventral compartment boundary, establishing planar polarity, spacing ommatidial clusters and cell fate specification (Baker, 2000; Blair, 1999; Cagan and Ready, 1989).
In this report, we now add a novel function to the Egfr and Notch signaling pathways: the initiation of the morphogenetic furrow. Our results suggest that both these pathways act upstream of both Hh and Dpp, but downstream of Wg. We also show that the processes that initiate pattern formation and those that propagate retinal development across the eye imaginal disc are genetically distinct from each other.
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MATERIALS AND METHODS |
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Temperature shift regimes
Egfrtsla/CyO and EgfrtopCO/CyO adults were mated and allowed to lay eggs for 1 hour at 18°C. Batches of their progeny were raised at 18°C, shifted to 28°C for 12 hours and then returned to 18°C. The 12 hour up-shift periods used were: 0-12, 12-24, 24-36, 36-48, 48-60, 60-72, 72-84, 84-96, 96-108, 108-120, 120-132, 132-144, 144-156, 156-168, 168-180, 180-192, 192-204 and 204-216 hours after egg deposition (AED). Temperature shifts that affected furrow initiation or disrupted compound eye structure are referred to as temperature-sensitive periods (TSP). Eye imaginal discs or adult eyes from at least 20 individuals were examined for each time point described below.
Immunohistochemistry
Antibodies used were rat -Elav (ONeill et al., 1994), mouse
-Wg (Brook and Cohen, 1996) and rabbit
-Dpp (Hoffmann and Goodman, 1987). Secondary antibodies were conjugated to FITC (Jackson Labs). F-actin was visualized with phalloidin conjugated to TRITC (Molecular Probes). Immunohistochemistry was performed essentially as described previously (Tomlinson and Ready, 1987).
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RESULTS |
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Removal of Egfr signaling during TSP1 (168 hours 180 hours AED) resulted in an adult eye that was devoid of ommatidia (compare Fig. 1B with 1C). We examined imaginal discs from TSP1 animals at both 192 hours and 204 hours AED. Instead of seeing a single Elav-positive column at 192 hours AED, and 8 at 204 hours AED, these discs lacked both ommatidia and the morphogenetic furrow, despite being returned to the permissive temperature for 12 and 24 hours, respectively (Fig. 1H,I). Removal of Egfr signaling during TSP2 (192 hours-204 hours AED) resulted in an adult eye with severe structural defects along the posterior-lateral margins (compare Fig. 1B with 1D). The ommatidia at the intersection of the equator and the posterior margin appear not to be affected. Imaginal discs from TSP2 animals were examined immediately at the end of TSP2 (204 hours AED) and while the furrow had clearly initiated at the posterior margin, its continued re-initiation along the lateral margins was inhibited (Fig. 1J). Subsequent removal of Egfr signaling also affects the development of the eye but these defects are not related to the birth or reincarnation of the morphogenetic furrow and have been described in an earlier report (Kumar et al., 1998).
It is important to note that between TSP1 and TSP2 there are 12 hours for which there is no requirement for Egfr function and that this period contains the time of furrow initiation (red line in Fig. 1A). Thus Egfr signaling is required before initiation to set up some mechanism that will act a few hours later and again subsequently for correct propagation of new columns along the lateral margins. We thus call these two temporally separable aspects of furrow initiation birth and reincarnation.
Is Egfr signaling sufficient to initiate the furrow?
The furrow initiating protein Dpp is expressed along the posterior-lateral margins (Heberlein and Moses, 1995; Heberlein and Treisman, 2000). We used a dppblk-GAL4 driver to express components of the Egfr pathway in this restricted expression domain for all of the experiments described (Fig. 2A; Blackman et al., 1991). By the late third instar, the furrow has progressed more than half way across the eye with about 20 columns of ommatidia in the wild type (Fig. 2B). Expression of wild-type and activated forms of the Egfr using the a dppblk-GAL4 driver resulted in the generation of ectopic retinal development along the lateral margins (Fig. 2C). This suggests that Egfr signaling is sufficient to direct the initiation of the morphogenetic furrow at this time and place and may be the critical regulator of a limiting checkpoint in normal development.
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The Egfr ligand Vein acts in wing vein patterning (Guichard et al., 1999) and another ligand Gurken acts in dorsal patterning of the oocyte (Nilson and Schüpbach, 1999), while the Spitz ligand functions along the embryonic midline and within the developing eye (Freeman, 1998; Perrimon and Perkins, 1997; Schweitzer and Shilo, 1997). We expressed all three ligands with the dppblk-GAL4 driver and only Spitz produced ectopic furrows (Fig. 2N,O). Star and Rhomboid (Rho) are thought to be upstream regulators of the positive acting ligand Spitz (Freeman, 1998; Schweitzer et al., 1995; Schweitzer and Shilo, 1997). We expressed Star and Rho individually and neither could induce ectopic furrow initiation (not shown) but together they act synergistically to cause ectopic initiation (Fig. 2P).
The published reports that describe the expression of the dppblk-GAL4 that is used in this report suggest that it would be the ideal driver for manipulating signaling at the posterior edge and margins of the eye imaginal disc. We confirmed the expression of the driver by crossing flies carrying the dppblk-GAL4 to flies harboring a UAS-lacZ construct and then assaying lacZ expression in both L2 and L3 eye discs (Fig. 3A,B). In both cases, lacZ is restricted to the posterior-lateral margins. This is in contrast to the wild type Dpp expression pattern in which Dpp leaves the margins after initiation and is found in cells within the advancing morphogenetic furrow (Curtiss and Mlodzik, 2000; Heberlein et al., 1993; Ma et al., 1993). We then induced ectopic furrows by expressing contitutively active Egfr along the margins via the dppblk-GAL4 driver and again assayed lacZ expression in this background. As we expected, lacZ remained along the posterior lateral margins. The expression of lacZ was highly elevated at the places along the dorsal and ventral margins where ectopic furrows had initiated (Fig. 3C). These results confirm that we are indeed restricting our analysis to the posterior-lateral margins and the elevated levels of lacZ at the sites of ectopic furrow initiation suggest that Egfr signaling is upstream of Dpp.
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The Hh, Dpp and Wg pathways are required for the initiation and progression of the morphogenetic furrow (Heberlein and Moses, 1995; Heberlein and Treisman, 2000). We have shown above that Egfr and Notch signaling also act in this process. dppblk-GAL4 driven Wg results in a block in both furrow birth and reincarnation (Fig. 6A). This inhibition is mediated by the receptor Frizzled2 (Fz2, Kennerdell and Carthew, 1998). Expression of a dominant negative Fz2 receptor along the margins blocks Wg signaling and results in ectopic furrow initiation (data not shown). Surprisingly, expression of a dominant negative Frizzled (Fz) receptor has no effect (data not shown), suggesting that the block on furrow initiation by Wg is mediated through Fz2 but not Fz.
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Hh and Dpp signaling act in the birth of the morphogenetic furrow at the posterior margin (Heberlein and Moses, 1995). However, it is not clear which is upstream of the other in this instance. We expressed these proteins with dppblk-GAL4 and neither could induce ectopic furrow. dppblk-GAL4 driven expression of the repressor isoform of Cubitus interuptus protein (CiR, which acts downstream of Hh) was unable to block furrow initiation (not shown) but a dominant negative version of Thick Veins (Tkv), the Dpp type I receptor, was sufficient to block furrow reincarnation but not birth (Fig. 6E). This effect was also achieved when dominant negative versions of Saxaphone (Sax), the other Dpp type I receptor, and Punt (Put) the Dpp type II receptor were expressed either individually or in combination. The effects are more dramatic if either type I receptor is removed simultaneously with the type II receptor, suggesting that there is some redundancy among these receptors during furrow initiation (data not shown). These results together with published reports (Chanut and Heberlein, 1997a; Curtiss and Mlodzik, 2000; Pignoni and Zipursky, 1997) suggest that that Hh role in furrow initiation is limited to birth and that Dpp may function in furrow reincarnation.
We have shown that loss of Notch signals blocks furrow initiation, while activated Egfr signaling promotes furrow initiation (Fig. 1). To establish epistasy we used dppblk-GAL4 to co-express dominant negative Notch with activated Egfr, Ras or Raf; in all cases furrow initiation was blocked (Fig. 6F). This suggests that the Notch pathway acts downstream of Raf in the Egfr pathway in this instance.
Do the ectopic furrows behave like the endogenous furrow?
During the progression of the furrow across the eye disc, Dpp is expressed in cells that are found within the furrow (Fig. 7A,A', Heberlein and Moses, 1995). In situations in which an ectopic furrow has been generated by overexpression of Egfr, cells within the ectopic furrows also express Dpp (Fig. 7B,B') indicating that Egfr is acting genetically upstream of Dpp. Using the Egfr conditional allele, we removed Egfr function from the advancing furrow and saw no effect on Dpp expression (Fig. 7C,C'). Normally, Wg is expressed in cells along the lateral margins just anterior to the morphogenetic furrow (Fig. 7D,D'; Ma and Moses, 1995). We have shown that Egfr appears to act genetically downstream of Wg signaling (Fig. 6A,B). In discs that contain ectopic furrows retinal development proceeds from the lateral margins despite the continued expression of Wg, further suggesting that Egfr signaling is downstream of Wg (Fig. 7E,E'). Surprisingly, when Egfr signaling was removed via our conditional allele, Wg expression was seen within the morphogenetic furrow (Fig. 7F,F').
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DISCUSSION |
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The Notch signaling pathway is known to antagonize Egfr signaling in many developmental contexts, even within the developing fly eye. However, we find that Notch does not antagonize Egfr signaling in furrow initiation and that Notch signaling is integrated within Egfr signaling downstream of Raf in this instance. We propose that Hh expression is the target of Egfr and Notch regulation at furrow birth, and that Hh but not Dpp constitutes the executive signal at this stage (Fig. 8). This is consistent with published observations of the role of Hh in this first phase of furrow induction (Borod and Heberlein, 1998; Dominguez and Hafen, 1997). We also suggest that Egfr and Notch target Dpp expression for reincarnation, and that Dpp but not Hh is the executive signal for this later phase of furrow induction (Fig. 8). This is consistent with published observations of the role of Dpp in furrow initiation (Burke and Basler, 1996; Chanut and Heberlein, 1997a; Chanut and Heberlein, 1997b; Curtiss and Mlodzik, 2000; Greenwood and Struhl, 1999; Heberlein et al., 1993; Horsfield et al., 1998; Ma et al., 1993; Pignoni and Zipursky, 1997; Wiersdorff et al., 1996).
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There are several examples of these pathways converging in some developmental decisions, while antagonizing each other in other instances. For example, during embryogenesis the Hh and Egfr pathways interact to specify head development (Amin et al., 1999). In the development of the adult abdomen, Wg, Dpp and Egfr pathways are integrated to produce a stereotyped dorsoventral pattern (Kopp et al., 1999), while Egfr and Dpp signals oppose each other to set up the operculum boundary (Dobens et al., 2000) and to distinguish between wing and leg disc fates (Kubota et al., 2000). We have shown that Notch signaling is genetically integrated into the Egfr pathway downstream of Raf. Our results indicate that during morphogenetic furrow initiation they cooperate. This provides one more example of the crucial interaction of the Notch and Egfr pathways in the regulation of development.
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ACKNOWLEDGMENTS |
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