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Toshiyuki Harumoto,2,
Kayoko Sakurai,4,
Ryu Ueda,5
Kaoru Saigo,6
Michael B. O'Connor,7,8 and
Hiroshi Nakato4,7*
Department of Earth and Planetary System Sciences, Graduate School of Science and Technology,1 Department of Sciences for Natural Environment, Faculty of Human Development, SORST,2 Japan Science and Technology Agency, Kobe University, Kobe,3 Department of Biology, Faculty of Science, Tokyo Metropolitan University, Hachioji,4 Genetic Strains Research Center, National Institute of Genetics, Mishima,5 Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan,6 Department of Genetics, Cell Biology, and Development,7 Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota8
Received 24 May 2004/ Returned for modification 6 July 2004/ Accepted 21 December 2004
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ABSTRACT |
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INTRODUCTION |
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Based on sequence identity and splice site conservation, Ss is the closest Drosophila homolog of the mammalian dioxin receptor (arylhydrocarbon receptor [Ahr]) (17, 27). Both mammalian and Drosophila proteins can also bind to the xenotoxin responsive element (XRE) and stimulate transcription from genes containing this cis-acting element (18). Although Ss has not been shown to bind to arylhydrocarbons, it regulates normal morphogenesis of the leg or antenna and bristles, all of which are major Drosophila sensor organs or tissues that respond to environmental chemicals.
Our results reveal that ectopic ss provokes a wing-to-leg and/or antenna homeosis that subsequently elicits apoptosis in an autonomous or nonautonomous manner. This apoptotic response is regulated by a novel transmembrane leucine-rich repeat (LRR) protein, Fili, and may be a common process induced by ectopic expression of various homeotic genes. These results indicate that homeosis elicits a complex set of signals that influence the survival of the transformed cells and their surrounding cells. In addition, these results suggest a hypothesis that different LRR family transmembrane proteins function in different subdomains of a developing field to recognize developmentally misspecified cells and to regulate cell survival.
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MATERIALS AND METHODS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The name fish-lips was derived from the observation that the expression pattern of fili in the wing disc made a fish lips-like shape. fili is identical to the temporarily assigned hypothetical gene CG4054 in the Berkeley Drosophila Genome Project. The fili-lacZ fly was identified during a screen of lacZ enhancer trap strains with P-lacW, a derivative of the transposon P-element (6). The fili mutant allele 
102 was isolated by an imprecise excision of P-lacW in fili-lacZ according to the standard procedure. The UAS-fili fly was made by inserting the fili cDNA (2,297 bp, including full-length open reading frame, 18 bp of the 5' untranslated region and 62 bp of the 3' untranslated region) into the pUAST vector (7) with a white+ marker and transforming the white– fly according to standard procedures.
The other lacZ enhancer trap lines we used are sdETX4, Dll01092, hth05745, hid05014, ombP1, fz3SW076-A7.3XW, trnS064117, and pucE69. hid05014 was also used as a mutant (see Fig. 4E and G). At the late-third-instar larval stage, this hid-lacZ is expressed irrespective of apoptosis around the dorsal-ventral boundary and at the two spots in the dorsal and ventral hinge region (data not shown). However, at the mid-third-instar larval stage, these expressions do not begin, and the expression is associated with apoptosis. Therefore, we observed the hepCA- or ss-induced hid-lacZ expression by using the mid-third-instar larvae.
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Antibodies. The other antibodies we used were rat anti-Al (from G. Campbell [1:1,000 dilution]), rat anti-Sal (from R. Barrio [1:400 dilution]), mouse anti-Dac (MABDAC2-3 from the Developmental Studies Hybridoma Bank [1:10 dilution of supernatant]), rabbit anti-Vg (from S. Carroll [1:200 dilution]), rabbit anti-p-Mad (PS1 from P. ten Dijke [1:200 dilution]), mouse anti-Arm (N2 7A1 from the Developmental Studies Hybridoma Bank [1:10 dilution of supernatant]), mouse anti-Dll (MAb DMDll.1 from D. Duncan [1:500 dilution]), and rabbit anti-Caps (from A. Nose [1:200 dilution]).
Mosaic overexpression analysis. Discs were prepared from larvae carrying the AyGAL4 (actin promoter-FRT-yellow+, terminator-FRT-GAL4 [28]), hs-FLP (yeast FLP recombinase gene driven by heat shock promoter), UAS-ss, and UAS-GFP transgenes. The GAL4-expressing clones were induced by heat treatment at 37°C for 20 min at 48 to 72 h after egg-laying and observed 48 to 72 h after heat treatment. In each experiment, we observed more than 10 wing discs to confirm the results.
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RESULTS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Overexpression of ss leads to a homeotic transformation from wing to ventral appendage before disappearance of the cells. ss is known to specify the identities of tarsus (distal leg) and arista (distal antenna) during normal development (17, 18). Thus, we thought that the ss overexpression in the wing may have removed the organ identity as a wing and underwent a homeotic change to a leg, antenna, or other ventral appendage that does not actually exist in the normal fly prior to disappearance of the wing. To investigate this possibility, we next examined the expression of marker genes specific to the wing or haltere or to leg or antenna. The sd gene, which is normally expressed exclusively in the wing and haltere (10) (Fig. 2A), was found to be less strongly expressed in ss-overexpressing clones (Fig. 2C and C'). This result suggests that the ss-overexpressing clones had lost, at least partially, their wing identity. In contrast, Dll, a master gene that directs the identity of the distal leg or whole antenna (13, 45) (Fig. 2A'), was ectopically and cell autonomously induced in the ss-overexpressing clones (Fig. 2D and D'). During normal wing development, Dll expression is induced in response to Wg signaling. However, Dll induction in the ss-overexpressing clones appeared to be independent of the Wg signal since Dfrizzled-3 (fz3) induction and Armadillo (Arm) accumulation did not coincide with the ss-overexpressing region, as demonstrated below. Therefore, we hypothesized that this Dll induction might provoke a different Dll function to redirect the identity of the wing to that of the distal leg or whole antenna. In fact, high-level induction of Dll in the wing has been reported to lead to its transformation into a distal leg (21). Although normal expression of ss in the leg is known to be downstream of Dll (17), Dll expression is regulated by ectopic ss in the wing, indicating the presence of a positive feedback loop between Dll and ectopic ss.
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We also obtained other evidence demonstrating that the cells with ss overexpression display characters of the ventral appendages. First, an ectopic appendage-like structure was often generated (Fig. 2I) when ss-induced apoptosis was partially inhibited by coexpression of Drosophila inhibitor of apoptosis protein 1 (DIAP1 [26]). The structure most similar to this appendage that is seen in external morphology of normal fly is the tarsus of leg (Fig. 2I'). Second, during normal development expression of patched (ptc) was dependent on Hedgehog signaling, which induces a band-like expression of dpp in the wing and the dorsal leg region and that of wg in the ventral leg region (5) (Fig. 2J and J'). When ss expression was induced by ptc-GAL4, Wg was ectopically induced only in the ventral half of the ptc-expressing region (Fig. 2K and K'), as found in the normal leg or antenna. However, the level of wg induction in the ptc-expressing region was weaker than that found in the normal leg. Therefore, the ss-expressing wing appears to have partially transformed its identity to that of a leg or antenna. This mixed or conflicted identity may also be responsible for induction of apoptosis. Although it has been shown previously that the ectopic expression of ss by ptc-GAL4 leads to a deletion of the central wing (17), the molecular mechanism was not identified. Our results suggest that the deletion is triggered primarily by homeotic transformation.
Overexpression of ss leads to apoptosis in which cell autonomy is position dependent. To study the detailed mechanism leading to apoptosis by ectopic expression of ss, we next examined the cell autonomy of apoptosis in ss-overexpressing clones. We monitored caspase-3 and JNK activation by using an antibody that recognizes active caspase-3 and the expression of a reporter gene, puckered (puc)-lacZ, respectively. After 48 h of mosaic induction, we observed two types of apoptosis (Fig. 3A). The ss-overexpressing clones inside the wing blade primordium showed strong activation of caspase-3 and a weak activation of JNK (Fig. 3A' and A"). Activation of caspase-3 in the vicinity of the dorsoventral compartment boundary (red line in Fig. 3A) was relatively weak and delayed. We can recognize the delay of the cell removal around the dorsoventral boundary more readily at later stage after the clone induction (data not shown). All of these responses were always cell autonomous. In contrast, the ss-overexpressing clones outside of the wing blade region (that is the hinge region) showed weak activation of caspase-3 and strong activation of JNK in cells on either side of the clone boundary (Fig. 3A'''). In this region, the outline of the clones which were probably induced at an earlier stage, are severely disrupted with strong activation of both caspase-3 and JNK (Fig. 3A'''').
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Coincidence of round shape and apoptotic response. Apoptosis in each of these regions was dependent on Hemipterous (Hep, an activator of JNK [20]), DIAP1, Head involution defective (Hid; a proapoptotic protein [23]) and Tgo (Fig. 4B to F). DIAP1 is known to degrade caspase through its ubiquitin-protein ligase activity. Hid can bind to DIAP1 to stimulate autoubiquitination of DIAP1, which prevents the degradation of caspase (58). Interestingly, the ss-overexpressing clones in hep or hid mutant or in DIAP1 overproducer backgrounds retained a round shape, as seen with ss-overexpressing clones in the wild-type background (Fig. 4A to E). In contrast, the ss-overexpressing clones in the tgo-RNAi background lost their round shape and invaded the surrounding normal cells (Fig. 4F). These results indicate that hep and hid only affect the apoptosis pathway, whereas tgo mediated events more upstream, such as the cell fate change induced by ss. Ectopic expression of ss may make a difference in cell affinity between the clones and surrounding normal cells, which leads to a round shape of the clones and subsequent apoptotic response.
Consistently, activation of JNK pathway by constitutively active Hep leads to hid expression (Fig. 4G). Besides, the ss-overexpressing clone induces hid expression autonomously in the wing blade region but nonautonomously in the wing hinge region (Fig. 4H).
Effect of ss overexpression on the intensity of Dpp and Wg signaling. The JNK-dependent cell death on either side of the clone boundary is quite similar to what has been referred to as "morphogenetic apoptosis," through which discontinuities in the Dpp and Wg morphogen activity gradients are corrected (2). We next examined the activities of certain morphogen signals in the vicinity of the ss-overexpressing clones. With regard to Dpp signaling, we can find a slight reduction in the expression of the lacZ enhancer trap of optomotor-blind (omb), a target gene of the Dpp signal (24) (see Fig. S1A' and B' in the supplemental material). However, the reduction is always found around the center of the clones and does not coincide with the outline of the clones. We also see a similarly moderate alteration of the level of phospho-Mad, an active form of the Dpp signal transducer "Mothers against dpp" (Mad) (48, 52, 57) (see Fig. S1A" and B" in the supplemental material). In the case of Wg signaling, we examined expression of the fz3-lacZ enhancer trap (51, 55), a target gene of the Wg signal, and the level of Arm (46, 54), a Wg signal transducer that is known to accumulate in response to the Wg signal (25, 47). We observed a reduction of fz3-lacZ expression interior to the clone boundary of the ss-overexpressing clones (see Fig. S1C, C', and D to D" in the supplemental material). However, in the most central cells, cytoplasmic accumulation of Arm was conversely observed (see Fig. S1C, C", D, and D' in the supplemental material). These results suggested that the level of Wg signal is not uniformly received throughout the ss-overexpressing clones and is not directly regulated by Ss. Similar responses were observed in clones both in the wing blade and in the hinge regions, as seen in Fig. S1C in the supplemental material. Taken together, these results indicate that discontinuities in the strength of Dpp and Wg signal reception does not precisely coincide with the boundary of the ss-overexpressing clones, suggesting that other factors contribute to the nonautonomous JNK activation in this case.
Position-dependent variance in the autonomy of apoptosis is found also in clones ectopically expressing homeotic genes. We next examined whether the position-dependent variance in cell autonomy of apoptosis is specific for ss-induced homeosis or a general trait exhibited by ectopic expression of diverse homeotic genes. The identity of each body segment is defined by a series of homeotic genes belonging to ANTP-C and BX-C. However, the Drosophila wing requires no input from ANTP-C and BX-C during its development (11). Instead, these homeotic genes repress wing development in all segments, except for the mid-thorax, where the wing normally develops. In order to produce a misspecified fate in wing cells, we expressed various homeotic genes in the wing discs. When labial (lab), proboscipedia (pb), Antennapedia (Antp), Ultrabithorax (Ubx), abdominal-A (abd-A), or Abdominal-B (Abd-B) were expressed by using sd-GAL4 driver, the adult wings showed abnormal vein patterns and incision of the wing margin (Fig. 5A to F). In the cases of Ubx or abd-A expression, wing incision was less frequently observed. In these cases, the wing has been shown to transform to an organ similar to a haltere (22). When mosaic clones expressing these homeotic genes are generated, JNK activation was found autonomously in the blade region but nonautonomously in the hinge region. All of these responses are quite similar to the results of ss overexpression, as has been described above. Thus, the position-dependent variance in cell autonomy of apoptosis may be a general phenomenon accompanying homeotic transformation.
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102, was isolated by imprecise excision of the P-element in fili-lacZ. It lacks 534 bp, including a part of the first exon, and is lethal at late embryonic stages. The main cause of this lethality is unknown. In the wing disc, fili exhibited a pattern of gene expression that was nearly complementary to that of Dll (Fig. 6A and B). In addition, fili expression was complementary to Dll expression in antenna discs (Fig. 6A" and B"). In contrast, in the leg disc, fili seemed to partially overlap with Dll (Fig. 6A' and B'). However, we found that most of the cells expressing the respective genes were in different layers of the leg disc folding.
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Shape and apoptosis of clones mutant for or overexpressing fili. Next, we examined the relationship of the clone shape and apoptosis in a simple fili mutant or in its overexpression. The fili mutant clones showed an irregular shape irrespective of their position in the wing disc (Fig. 10A) and did not display any apoptotic signs. These results are not always discrepant from the other results and are similar to observations in mutants for caps or trn alone (38). The other LRR family proteins might function with Fili in a redundant manner in the generation of affinity with surrounding normal cells. In contrast to the fili mutant, the fili-overexpressing clones showed a smooth outline (Fig. 10B). The smooth outlines were found even where endogenous fili was expressed, which may be due to the immense amount of its expression by using UAS/GAL4 system. However, the clone in the central region where endogenous fili was not expressed exhibited the most rounded shape (Fig. 10B'). Interestingly, unlike the case of caps and trn, the overexpression of fili alone induced apoptosis in a nonautonomous manner. When UAS-fili was induced by ptc-GAL4 (Fig. 10D), nonautonomous activation of JNK was apparent in the cells around the posterior edge of ptc expression but not in the cells around the anterior edge (Fig. 10D to D"). The posterior edge is known to create a sharp discontinuity of ptc expression levels, whereas the anterior edge does not (5). More interestingly, the area where JNK was activated did not overlap the area where endogenous fili was expressed. As a result, the areas with JNK activation were divided into three regions (arrowheads in Fig. 10D"). Also, forced expression of fili in the central wing blade in the adult wing generated a severely notched phenotype by apoptosis (Fig. 10C). These data strongly suggest that the occurrence of a large discontinuity in the fili expression level activates JNK nonautonomously.
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DISCUSSION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ss-induced autonomous apoptosis is related to cell competition. Cell competition is a phenomenon whereby cell clones with a slow growth rate are eliminated during development. The autonomous cell death in cell competition has been demonstrated to be caused by an impaired reception of extracellular survival factors. As representative examples, clones with cells heterozygous for the M(2)60E mutation show an autonomous death as a result of reduced Dpp reception (40). Thus, the autonomous death in ss-overexpressing cells in the wing blade might be a type of cell competition response. In this case, however, the extracellular factor that the ss-overexpressing cells fail to receive is not likely to be Dpp, since we observed that the Dpp signaling level is not strongly affected in the ss-overexpressing cells (see Fig. S1A and B in the supplemental material). Also, ss-overexpressing cells can be removed from the lateral region of the wing blade where the level of Dpp signaling is normally low. In contrast, cells heterozygous for M(2)60E can survive in this area due to the loss of competition for Dpp (40). Therefore, Wg or other extracellular survival factors might be affecting the survival of ss-overexpressing cells, as discussed below.
Position-dependent variance in cell autonomy is found in the apoptotic response to ss overexpression. We have not yet addressed the question of why the variance in cell autonomy of ss-induced apoptosis is related to dorsoventral patterning or blade/hinge subdomains. However, the variance suggests an interesting model in which signals that normally regulate dorsoventral appendage patterning or blade/hinge subdomains also directly affect the apoptotic response or specification of organ identity as cryptic mechanisms. Interestingly, ectopic expression of most of the segment-specifying homeotic genes commonly shows a similar position-dependent variance in cell autonomy (Fig. 5). In this view, Wg, the morphogen controlling the dorsoventral patterning (42, 60), or Vg, the selector of wing subdomain (31, 34), may be involved in the regulation of position-dependent variance in the cell autonomy of apoptosis. However, definitively demonstrating the involvement of Wg or Vg is difficult because changing Wg signal or Vg activity alone also induces a severe unrelated apoptosis (2). Thus, the simultaneous manipulation of ss and Wg/Vg activities may lead to a complicated result that is difficult to interpret.
Implication of various LRR family transmembrane proteins in the regulation of apoptosis to remove misspecified cells. A recent study concerning the relation of apoptosis in sal-overexpressing cells and LRR family proteins Caps/Trn has provided a new insights into how cell survival of misspecified cells is controlled (38). Cells that overexpress sal lack caps/trn expression and are removed from the area where sal is not normally expressed. However, cells expressing both sal and caps can survive. In order to control cell survival in the wing, Caps and Trn presumably provide position-dependent recognition cues along the anteroposterior axis, whereas Fili appears to provide such cues to neighboring cells along the dorsoventral axis. These results raise the possibility that cells can recognize the type of neighboring cells using distinct LRR family members, depending on the position of the cells in the primordial tissues. The Drosophila genome contains at least 10 members of LRR family, most of which have not been examined for function (Flybase).
Functional relationship between Drosophila Ss and mammalian Ahr. In the present study, several cellular responses to ss overexpression have been described. Clonal overexpression of ss induces a sequential response composed of an induction of leg- or antenna-specific genes, autonomous homeosis, rounding, and autonomous or nonautonomous apoptosis. The activation of mammalian Ahr is known to affect apoptosis, cell proliferation, differentiation, and morphogenesis in various tissues (50). Polycyclic aromatic hydrocarbon, a ligand for Ahr, induced apoptosis accompanied by the activation of JNK (33). It should also be noted that dioxin-induced responses such as P450 expression in the liver are not observed in all cells exposed to dioxin but are observed in a subset of centrilobular cells with the highest sensitivity to dioxin (4). Thus, the mosaic activation of Ss and subsequent JNK activation in surrounding cells in Drosophila induce circumstances similar to that of liver cells exposed to dioxin. With regard to morphogenesis, the type of morphogenetic signals that are modified or distorted during dioxin action is unknown, despite many examples of dioxin-induced mismorphogenesis that have been reported. Therefore, our studies on Ss in Drosophila may provide at least in part, a common molecular and cellular basis for understanding Ahr-induced apoptosis and mismorphogenesis. It could involve homeotic transformation of organ identity, recognition by surrounding cells through LRR protein, and apoptosis-mediated large deletion of tissues that can cause a malformation during organogenesis. Interestingly, all of the genes involved in this sequential process are evolutionarily conserved in mammals. Similar and detailed analysis in mammalian system will resolve these issues.
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ACKNOWLEDGMENTS |
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This study was supported by grants from the Japan Science and Technology Agency; the Ministry of Education, Science, Sports, and Culture in Japan (to T.A.-Y.); and NIH and the Human Frontier Science Program (to H.N.). M.B.O. is an Investigator of the Howard Hughes Medical Institute.
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FOOTNOTES |
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Supplemental material for this article may be found at http://mcb.asm.org/.
T.A.-Y., T.H., and K.S. contributed equally to this study.
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