ftz-f1

DEVELOPMENTAL BIOLOGY

Embryonic

FTZ-F1 mRNA of 5.2 kb is likely to be of maternal origin, present from 0 to 4 hour embryos, consistent with the period of FTZ-F1 activity and the expression of fushi tarazu in early embryos. FTZ-F1 mRNA is not detectable from 4 to 14 hours of development, but reappears in 14-22 hour embryos. The late mRNA species are slightly different in size (5.6 and 4.8 kb), suggesting that they are modified at the transcriptional or posttranscriptional level. The reappearance of FTZ-F1 DNA binding activity at a time when ftz is silent suggests that FTZ-F1 has a function distinct from the activation of ftz (Lavorgna, 1993).

Larval and Pupal

FTZ-F1, a member of the nuclear receptor superfamily, has been implicated in the activation of the segmentation gene fushi tarazu during early embryogenesis of Drosophila. An isoform of FTZ-F1, ßFTZ-F1, is expressed in the nuclei of almost all tissues slightly before the first and second larval ecdysis and before pupation. The tissue distribution of ßFTZ-F1 protein was examined by immunostaining. An antibody against ßFTZ-F1 stains the nuclei of most larval tissues at 44-46 hours AEL -- for example, the salivary gland, fat body, trachea, ring gland, epidermis, guts and Malpighian tubules. Staining of gonads was not detectable. Similar nuclear staining patterns are observed in stage-16 embryos, larvae at approximately 72 hours AEL and prepupae at 9 hours APF. No staining was observed in either prepupal tissues at 4 hours APF or larval tissues at 60-63 hours AEL, consistent with the temporal expression profile described above. These results clearly show that ßFTZ-F1 is expressed in most tissues during particular stages and that the protein is localized to the nucleus (Yamada, 2000).

Severely affected ftz-f1 mutants display an embryonic lethal phenotype, but can be rescued by ectopic expression of ßFTZ-F1 during the period of endogenous ßFTZ-F1 expression in the wild type. The resulting larvae are not able to molt, but this activity is rescued again by forced expression of ßFTZ-F1, allowing progression to the next larval instar stage. However, premature expression of ßFTZ-F1 in wild-type larvae at mid-first instar or mid-second instar stages causes defects in the molting process. Sensitive periods were found to be around the time of peak ecdysteroid levels and slightly before the start of endogenous ßFTZ-F1 expression. A hypomorphic ftz-f1 mutant that arrests in the prepupal stage can also be rescued by ectopic, time-specific expression of ßFTZ-F1. Failure of salivary gland histolysis, one of the phenotypes of the ftz-f1 mutant, is rescued by forced expression of the ftz-f1 downstream gene Br-C during the late prepupal period. These results suggest that ßFTZ-F1 regulates genes associated with ecdysis and metamorphosis, and that the exact timing of its action in the ecdysone-induced gene cascade is important for proper development (Yamada, 2000).

FTZ-F1 functions in cuticle formation. The insect cuticle is composed of layers of film. Sequential formation of different layers (cuticlin, epicuticle and endocuticle), is observed beginning approximately 12 hours before the next ecdysis. ßFTZ-F1 is expressed after a new epicuticle layer for the next instar appears. Premature expression of ßFTZ-F1 induces disruption of the epicuticle. These observations highlight the importance of ßFTZ-F1 in the formation of normal cuticle structure and suggest that some of the target genes of ßFTZ-F1 are involved in the process of cuticle formation. In particular, the importance of the timing of expression of these genes is demonstrated. It has been shown that some pupal cuticle proteins are expressed in a stage-specific manner during prepupal periods. ßFTZ-F1 regulates the EDG78E and EDG84A genes, which encode putative pupal cuticle proteins. These observations suggest that ßFTZ-F1 is responsible for the stage-specific expression of cuticle proteins during the prepupal stage (Yamada, 2000).

Analysis of FTZ-F1 transcription during larval and prepupal development shows the appearance of the 5.6- and 4.8-kb FTZ-F1 RNAs (corresponding to the late mRNA species) at 6-8 hours of prepupal development, identical to the timing and level of puffing at puff 75CD (Lavorgna, 1993).

Temporal profiles of nuclear receptor gene expression reveal coordinate transcriptional responses during Drosophila development

Many of the 21 members of the nuclear receptor superfamily in Drosophila are transcriptionally regulated by the steroid hormone ecdysone and play a role during the onset of metamorphosis, including the EcR/USP ecdysone receptor heterodimer. The temporal patterns of expression for all detectable nuclear receptor transcripts were examined throughout major ecdysone-regulated developmental transitions in the life cycle: embryogenesis, a larval molt, puparium formation, and the prepupal-pupal transition. An unexpected close temporal relationship was found between DHR3, E75B, and betaFTZ-F1 expression after each major ecdysone pulse examined, reflecting the known cross-regulatory interactions of these genes in prepupae and suggesting that they act together at other stages in the life cycle. In addition, E75A, E78B, and DHR4 are expressed in a reproducible manner with DHR3, E75B, and betaFTZ-F1, suggesting that they intersect with this regulatory cascade. Finally, known ecdysone-inducible primary-response transcripts are coordinately induced at times when the ecdysteroid titer is low, implying the existence of novel, as yet uncharacterized, temporal signals in Drosophila (Sullivan, 2003).

Total RNA was isolated from two independent collections of embryos staged at 2-h intervals throughout the 24 h of Drosophila embryonic development. Five Northern blots were prepared using equal amounts of RNA from each time point. These blots were sequentially hybridized, stripped, and rehybridized with radioactive probes derived from each of the 21 nuclear receptor genes encoded by the Drosophila genome. This approach allowed the generation of time courses of nuclear receptor gene expression that could be directly compared between family members. The transcripts detected are consistent with reported sizes. Transcripts from eight nuclear receptor genes were not detectable during embryonic development: E75C, E78, CG16801, DHR38, DHR83, dsf, eg, and svp (Sullivan, 2003).

Transcripts from nine nuclear receptor genes can be detected at the earliest time point (0-2 h): usp, EcR-A, FTZ-F1, DHR39, DHR78, DHR96, dERR, dHNF-4, and tll. This expression is consistent with the known maternal contribution of usp, EcR, and FTZ-F1. The observation that transcripts from DHR39, DHR78, DHR96, dERR, and dHNF-4 are undetectable by the next time point examined (2-4 h) suggests that these mRNAs are maternally loaded and rapidly degraded. EcR-B and usp transcripts are induced in early embryos, up-regulated at 6-8 h after egg laying (AEL), and maintain expression through the end of embryogenesis, with down-regulation of EcR-B in late embryos. EcR-A, in contrast, is expressed for a relatively brief temporal window, at 8-14 h AEL (Sullivan, 2003).

Six nuclear receptor genes are expressed in brief intervals during midembryonic stages. DHR39 and E75A are initially induced at 4-6 and 6-8 h AEL, respectively, and peak at 8-12 h AEL. This is followed by induction of DHR3, DHR4, and E75B at 8-12 h AEL, followed by ßFTZ-F1 expression at 12-18 h AEL. DHR39 appears to exhibit an expression pattern reciprocal to that of ßFTZ-F1, with lowest levels of mRNA at 14-16 h AEL and reinduction at 16-18 h as ßFTZ-F1 is repressed. This is followed by a second peak of E75A transcription at 18-22 h AEL (Sullivan, 2003).

A second group of nuclear receptors, DHR78, DHR96, dHNF-4, and dERR, is more broadly expressed at low levels throughout embryogenesis. DHR78 accumulates above its constant low level of expression between 8 and 14 h AEL. dERR exhibits an apparent mRNA isoform switch between 14 and 18 h AEL. dHNF-4 regulation also appears complex, with two size classes of mRNA induced at approximately 8-10 h AEL. While the 4.6-kb dHNF-4 mRNA is expressed throughout embryogenesis, the 3.3-kb mRNA is down-regulated at 14-16 h AEL. This timing is consistent with observations that dHNF-4 is expressed primarily in the embryonic midgut, fat body, and Malpighian tubules. Finally, nuclear receptors known to exert essential functions in patterning the early embryo, tll, kni, and knrl, are expressed predominantly during early stages (Sullivan, 2003).

Two genes that are not members of the nuclear receptor superfamily, BR-C and E74, were also examined in this study, as transcriptional markers for ecdysone pulses during development. Unexpectedly, both of these genes are induced late in embryogenesis, several hours after the rise in ecdysone titer at 6 h AEL. An approximately 7-kb BR-C transcript is induced at 10-12 h AEL and is present through the end of embryogenesis while E74B is induced at 14-16 h AEL and repressed as E74A is expressed from 16-20 h AEL. This BR-C expression pattern is consistent with the identification of the BR-C Z3 isoform in specific neurons of the embryonic CNS (Sullivan, 2003).

First-instar larvae were synchronized as they molted to the second instar, aged and harvested at 4-h intervals throughout second-instar larval development. Two Northern blots were prepared using equal amounts of total RNA isolated from a single collection of animals. Each blot was sequentially hybridized, stripped, and rehybridized to detect nuclear receptor transcription. The following transcripts were not detectable during the second instar: E75C, dERR, CG16801, DHR83, dsf, eg, svp, tll, kn, and knrl (Sullivan, 2003).

EcR-B expression is induced in mid-second-instar larvae, but does not reach maximum levels until 68-72 h AEL, just before the molt. In contrast, usp is expressed throughout the instar. A sequential pattern of nuclear receptor expression is observed that resembles the pattern seen in midembryogenesis. DHR39 and E75A are expressed in the early second instar. This is followed by induction of E75B, E78B, DHR3, and DHR4, followed by expression of ßFTZ-F1 at the end of the instar. DHR39 again shows a pattern that is approximately reciprocal with ßFTZ-F1, with highest levels during the first half of the instar. Similarly, DHR78, DHR96, and dHNF-4 exhibit broad expression patterns throughout second-instar larval development. E74A, E75A, and DHR38 are coordinately up-regulated with EcR-B at the end of the instar, between 64-72 h AEL. Finally, an approximately 9-kb BR-C transcript is detected throughout the second-larval instar (Sullivan, 2003).

Nuclear receptor gene expression was also examined throughout the third larval instar and into the early stages of metamorphosis, encompassing the ecdysone-triggered larval-to-prepupal and prepupal-to-pupal transitions. Third-instar larvae were staged relative to the molt from the second instar and harvested at 4-h intervals throughout the 48 h of the instar. Prepupae were synchronized relative to puparium formation (±15 min) and harvested at 2-h intervals up to 16 h after puparium formation (APF). Total RNA was isolated from whole animals and analyzed by Northern blot hybridization. Five blots were prepared from two independent collections of animals. These blots were sequentially hybridized, stripped, and rehybridized to detect nuclear receptor gene expression. The following transcripts were not detectable during third-instar larval or prepupal stages: CG16801, DHR83, dsf, eg, svp, tll, kn, and knrl (Sullivan, 2003).

Most nuclear receptor genes show little or no detectable expression in early and mid-third-instar larvae, a time when the ecdysone titer is low. Similar to the pattern seen in second-instar larvae, usp is expressed at relatively low levels throughout the instar and up-regulated at puparium formation, while EcR-B is induced at approximately 100 h AEL and rapidly down-regulated at puparium formation. This is followed by a sequential pattern of nuclear receptor expression similar to that seen at earlier stages. DHR39, E75A, and E78B are induced at 116-120 h AEL, in concert with the late larval ecdysone pulse, followed by maximum accumulation of E75B, DHR3, and DHR4 at 0-4 h APF. ßFTZ-F1 is expressed from 6-10 h APF, with a pattern that is approximately reciprocal to that of DHR39. EcR-A is expressed in parallel with E75B, DHR3, and DHR4 in midprepupae, similar to their coordinate expression during embryogenesis (Sullivan, 2003).

DHR78, DHR96, and dHNF-4 continue to exhibit broad expression profiles throughout third-instar larval and prepupal development. An E75 isoform not detected in embryos or second-instar larvae, E75C, is also detectable at low levels throughout most of the third instar and up-regulated in correlation with the late-larval and prepupal pulses of ecdysone. DHR38 is detectable at very low levels in early third-instar larvae, in synchrony with the early induction of E74B and BR-C. E74B is repressed, E74A is induced, and BR-C transcripts are up-regulated in late third-instar larvae, in synchrony with the late-larval ecdysone pulse. The prepupal pulse of ecdysone occurs at 10-12 h APF, marking the prepupal-to-pupal transition. EcR-A, E75A, E78B, DHR4, dERR, E75C, dHNF-4, and E74A are all induced at 10-12 h APF, in apparent response to this hormone pulse. These results are consistent with a microarray analysis of gene expression at the onset of metamorphosis where the temporal profiles of about half of these genes have been reported (Sullivan, 2003).

Most nuclear receptors can be divided into one of four classes based on this study: (1) those that are expressed exclusively during early embryogenesis (kni, knrl, tll); (2) those that are expressed throughout development (usp, DHR78, DHR96, dHNF-4); (3) those that are expressed in a reproducible temporal cascade at each stage tested (E75A, E75B, DHR3, DHR4, FTZ-F1, DHR39), and (4) those that are undetectable in these assays (CG16801, DHR83, dsf, eg, svp) (Sullivan, 2003).

Three nuclear receptor genes appear to be expressed exclusively during early embryogenesis: kni, knrl, and tll. This restricted pattern of expression fits well with the functional characterization of these genes, which have been shown to act as key determinants of embryonic body pattern. Eight genes (usp, EcR, FTZ-F1, DHR39, DHR78, DHR96, dERR, and dHNF-4) were identified that appear to have maternally deposited transcripts and thus possible embryonic functions. Indeed, maternal functions have been defined for usp, EcR, and alphaFTZ-F1 (Sullivan, 2003).

Four nuclear receptor genes are broadly expressed through all stages examined: usp, DHR78, DHR96, and dHNF-4. dHNF-4 mRNA is first detectable at 6-10 h AEL, as the ecdysone titer begins to rise. In addition, peaks of dHNF-4 expression are seen at 0, 12, and 16 h APF, in synchrony with the E74 and E75C early ecdysone-inducible genes. These observations raise the interesting possibility that this orphan nuclear receptor is regulated by ecdysone (Sullivan, 2003).

DHR38 transcripts are difficult to detect in these assays. This is consistent with studies which used RT-PCR or riboprobes for this purpose. Nonetheless, DHR38 mRNA can be detected during third-instar larval development, consistent with the widespread expression reported in earlier studies. DHR38 expression peaks at late pupal stages, consistent with its essential role in adult cuticle formation (Sullivan, 2003).

dERR and E75C display related temporal profiles of expression that do not fit with other nuclear receptor genes described in this study. Both of these genes are specifically transcribed during prepupal development, with increases in expression at 0 and 10-12 h APF. dERR, but not E75C, is also expressed during embryogenesis, with an initial induction at approximately 6 h AEL. These increases occur in synchrony with ecdysone pulses, suggesting that these orphan nuclear receptor genes are hormone inducible, although in a stage-specific manner. Further studies of dERR regulation, as well as a genetic analysis of this locus, are currently in progress (Sullivan, 2003).

Interactions between the DHR3 and E75B orphan nuclear receptors contribute to appropriate ßFTZ-F1 regulation during the onset of metamorphosis. DHR3 is both necessary and sufficient to induce ßFTZ-F1 and appears to exert this effect directly, through two response elements in the ßFTZ-F1 promoter. E75B can heterodimerize with DHR3 and is sufficient to block the ability of DHR3 to induce ßFTZ-F1. These three factors thus define a cross-regulatory network that contributes to the timing of ßFTZ-F1 expression in midprepupae. ßFTZ-F1, in turn, acts as a competence factor that directs the appropriate genetic and biological responses to the prepupal pulse of ecdysone. The patterns of DHR3, E75B, and ßFTZ-F1 expression observed at the onset of metamorphosis are consistent with these regulatory interactions as well as the expression patterns reported in earlier studies (Sullivan, 2003).

Unexpectedly, the tight linkage of DHR3, E75B, and ßFTZ-F1 expression seen at the onset of metamorphosis is recapitulated at earlier stages, after each of the major ecdysone pulses examined, in midembryogenesis and second-instar larval development. This observation suggests that the regulatory interactions between these receptors is not restricted to metamorphosis, but rather may recur in response to each ecdysone pulse during development. It is possible that this regulatory cascade contributes to cuticle deposition, which is dependent on ecdysone signaling in embryos, larvae, and prepupae. In support of this proposal, DHR3 and ßFTZ-F1 mutants exhibit defects in larval molting, suggesting that they act together to regulate this early ecdysone response (Sullivan, 2003).

Three other orphan nuclear receptor genes, E75A, DHR4, and DHR39, are expressed in concert with DHR3, E75B, and ßFTZ-F1, after the embryonic, second-instar, and third-instar ecdysone pulses. A peak of E75A expression marks the start of each genetic cascade, correlating with the rising ecdysone titer in 6- to 8-h embryos, the first half of the second instar, and in late third-instar larvae. This is followed by DHR3, E75B, and DHR4 expression which, in turn, is followed by a burst of ßFTZ-F1 expression. E78B is expressed in synchrony with DHR4 in late second and third-instar larvae, but not in embryos. These patterns of expression raise the interesting possibility that E75A, DHR4, and E78B may intersect with the cross-regulatory network defined for DHR3, E75B, and ßFTZ-F1. E75B and E78B are related to the Rev-erb vertebrate orphan nuclear receptor and are both missing their DNA binding domain. E75B and E78B null mutants are viable and fertile, suggesting that they exert redundant regulatory functions. E75A mutants die during larval stages, with no known direct regulatory targets. DHR4 mutants have not yet been described, although recent work indicates that this gene exerts essential roles in genetic and biological responses to the late larval ecdysone pulse. Further functional studies of these nuclear receptor genes should provide insight into their possible contribution to the regulatory circuit defined by DHR3, E75B, and ßFTZ-F1 (Sullivan, 2003).

Interestingly, DHR39 displays a reproducible pattern of expression that is inversely related to that of ßFTZ-F1, defining possible repressive interactions. DHR39 and ßFTZ-F1 have a similar DNA binding domain (63% identity) and bind to identical response elements, suggesting that they may exert cross-regulatory interactions. Moreover, DHR39 can repress transcription through the same response element that is activated by ßFTZ-F1. It would be interesting to determine whether the reciprocal patterns of DHR39 and ßFTZ-F1 expression during development is of functional significance (Sullivan, 2003).

The transcription of BR-C, EcR, E74, and E75 has been extensively characterized during the onset of metamorphosis, due to their rapid and direct regulation by the steroid hormone ecdysone at this stage in development. Surprisingly, however, their expression appears to be disconnected from the high-titer ecdysteroid pulses during embryonic and second-instar larval stages. As expected, EcR is induced early in embryonic development, in coincidence with the rising ecdysone titer at 4-10 h AEL, with EcR-B transcripts appearing first followed by EcR-A. BR-C mRNA, however, is not seen until 10-12 h AEL and E74B mRNA is induced even later, at 14-16 h AEL, when the ecdysteroid titer has returned to a basal level. Both EcR-B and E74B are repressed from 16-20 h AEL as E74A and E75A are induced, a switch that has been linked to the high-titer ecdysone pulse in late third-instar larvae; however, this response occurs during late embryogenesis when the ecdysteroid titer is low. A similar observation has been made for E75A expression in the Manduca dorsal abdominal epidermis, where a brief burst of E75A mRNA is detected immediately before pupal ecdysis, after the ecdysteroid titer has returned to basal levels (Sullivan, 2003).

It thus seems likely that the second instar ecdysone pulse occurs during the first half of the instar. This profile is consistent with the early induction of E75A. EcR-B and E74A, however, are not induced until the second half of the second instar, with a peak at the end of the instar. BR-C mRNA levels remain steady throughout the second instar. Finally, EcR-B, E74B, and BR-C are induced in early to mid-third-instar larvae, a time when one or more low-titer ecdysone pulses may occur. It is curious that E74B is poorly expressed relative to E74A during embryonic and second-instar larval stages, disconnecting its expression from that of EcR. This pattern is not seen in studies that focused on the onset of metamorphosis. Taken together, the temporal profiles of early gene expression (EcR, BR-C, E74, E75A) during late embryonic and late second-instar larval stages appear to be unlinked to the known ecdysteroid pulses at these stages. This could indicate that these promoters are activated in a hormone-independent manner at these stages in the life cycle. Alternatively, these ecdysone primary-response genes may be induced by a novel temporal signal that remains to be identified (Sullivan, 2003).

Several lines of evidence indicate that 20-hydroxyecdysone is not the only temporal signal in Drosophila. A major metabolite of this hormone, 3-dehydro-20-hydroxyecdysone, was shown to be as effective as 20-hydroxyecdysone in inducing target gene transcription in the hornworm, Manduca sexta. Similarly, 3-dehydro-20-hydroxyecdysone is more efficacious than 20-hydroxyecdysone in inducing Fbp-1 transcription in the Drosophila larval fat body. A high-titer pulse of alpha-ecdysone, the precursor to 20-hydroxyecdysone, can drive the extensive proliferation of neuroblasts during early pupal development in Manduca. This is the first evidence that alpha-ecdysone is responsible for a specific response in insects. It is unlikely, however, that this signal is transduced through the EcR/USP heterodimer, which shows only very low transcriptional activity in response to this ligand. Rather, recent evidence indicates that alpha-ecdysone may activate DHR38 through a novel mechanism that does not involve direct hormone binding (Sullivan, 2003).

Studies of ecdysteroid-regulated gene expression in Drosophila have also provided evidence for hormone signaling pathways that may act independently of 20-hydroxyecdysone. Several studies have identified a large-scale switch in gene expression midway through the third larval instar, an event that has been referred to as the mid-third-instar transition. It is not clear whether this response is triggered by a low-titer ecdysteroid pulse, another hormonal signal, or in a hormone-independent manner. Similarly, the let-7 and miR-125 micro-RNAs are induced at the onset of metamorphosis in Drosophila in tight temporal correlation with the E74A early mRNA, but not in apparent response to 20-hydroxyecdysone. These studies indicate that 20-hydroxyecdysone cannot act as the sole temporal regulator during the Drosophila life cycle (Sullivan, 2003).

Effects of mutation or deletion

Ectopic expression of ftz-f1 at first instar, late second instar or early prepupal periods causes developmental defects. The sensitive stages slightly precede the endogenous ftz-f1 expression times. Premature expression at late second instar causes a failure in the second ecdysis, though third instar mouthooks and anterior spiracles form. Premature expression of ftz-f1 induces the Edg78E and Edg84A genes, which contain strong FTZ-F! binding sites upstream of their transcription start sites (Ueda, 1995).

In Drosophila, fluctuations in 20-hydroxyecdysone (ecdysone) titer coordinate gene expression, cell death, and morphogenesis during metamorphosis. It has been hypothesized that ßFTZ-F1 (an orphan nuclear receptor) provides specific genes with the competence to be induced by ecdysone at the appropriate time, thus directing key developmental events at the prepupal-pupal transition. This study examines the role of ßFTZ-F1 in morphogenesis. A detailed study has been made of morphogenetic events during metamorphosis in control and ßFTZ-F1 mutant animals. Leg development in ßFTZ-F1 mutants proceeds normally until the prepupal-pupal transition, when final leg elongation is delayed by several hours and significantly reduced in the mutants. ßFTZ-F1 mutants fail to fully extend their wings and to shorten their bodies at the prepupal-pupal transition. ßFTZ-F1 mutants are unable to properly perform the muscle contractions that drive these processes. The muscular contractions believed to drive leg extension, as well as head eversion and wing extension, are thought to do so by causing an increase in the internal pressure of the animal. The inflation and extension of the legs and wings is thought to require the generation of greater pressure inside the developing legs than outside. Several defects can be rescued by subjecting the mutants to a drop in pressure during the normal time of the prepupal-pupal transition. These findings indicate that ßFTZ-F1 directs the muscle contraction events that drive the major morphogenetic processes during the prepupal-pupal transition in Drosophila (Fortier, 2003).

Therefore, wildtype ßFTZ-F1 function is not required for morphogenetic processes that occur during the late larval and early prepupal stages. At 0 h APF, ßFTZ-F1 mutant leg discs appear normal, suggesting that ßFTZ-F1 has no role in leg disc development prior to the beginning of metamorphosis. Leg discs examined at 6 h APF also show no defects in length or in the cell shape changes required for the first phase of elongation, indicating that ßFTZ-F1 is not involved in these early metamorphic events. The ßFTZ-F1 allele used in this study, FTZ-F1¹⁷, is hypomorphic and is expressed at very low levels. It is possible that these cell shape changes require only a minute amount of ßFTZ-F1 and would not occur normally in the complete absence of this protein. Although this is a formal possibility, the evidence indicates that it is unlikely given the developmental expression pattern of ßFTZ-F1. ßFTZ-F1 is expressed during the last larval molt (approximately 48 h before puparium formation), but is not expressed again until the mid-prepupal stage, beginning at about 5 h APF (Fortier, 2003).

ßFTZ-F1 mutant legs develop normally until the prepupal-pupal transition. In the mutant, the anterior translocation and subsequent extension of the legs are delayed by several hours and are incomplete. All subsequent leg development in the mutant appears to occur normally, indicating that the abnormalities seen in these mutants are in fact due to stage-specific defects, rather than to general weakness or ill-health (Fortier, 2003).

In wild-type animals, during the prepupal-pupal transition, contractions of larval muscles shorten the prepupal body, translocate the mid-abdominal gas bubble to the posterior end of the pupal case, and then move the gas to the anterior, providing a space into which the head can evert. These contractions have long been thought to generate hydrostatic pressure, inflating and elongating the legs and wings in the animal. Detailed observation of the ßFTZ-F1 mutants in this study reveal defects in each of these developmental processes. Furthermore, in ßFTZ-F1 mutants, the muscle contractions that drive these events are much less deliberate, vigorous, and consistent than in controls (Fortier, 2003).

Thus bubble translocation, leg and wing elongation, and head eversion can be rescued by exposing mutant prepupae to decreased external pressure. This indicates that these defects result from failure to generate sufficient internal pressure at the appropriate time. This also provides direct evidence that hydrostatic pressure does in fact drive the major extensions of legs and wings at the prepupal-pupal transition. The observation that a drop in pressure can completely rescue leg elongation in some ßFTZ-F1 mutants suggests that there are no defects in the leg imaginal discs of these animals and indicates that ßFTZ-F1 is required for the muscle contractions that drive major morphogenetic events at the prepupal-pupal transition. To test the possibility that abnormalities in muscle morphology account for these contractile defects, both light microscopy and transmission electron microscopy (TEM) studies were performed, comparing musculature of control and ßFTZ-F1 mutant animals up to 12 h APF. No muscle differences have been detected between control and mutant animals (Fortier, 2003).

The increase in hydrostatic pressure that inflates and elongates the wings and legs during pupation normally occurs when the surrounding pupal cuticle is still incomplete. During wild-type metamorphosis, the development of the pupal cuticle is completed shortly after the prepupal-pupal transition. Therefore, in ßFTZ-F1 mutants, it is possible that the delay in muscle contraction results in this transition taking place within a rigid pupal cuticle, which does not allow complete head eversion, or extension of wings and legs. Another possibility is that abnormal cuticle formation or deposition may affect some events at pupation. The expression of EDG78E and EDG84A, genes that encode pupal cuticle proteins, is reduced and delayed in ßFTZ-F1 mutants. If these proteins are not expressed properly, the cuticle may be abnormally rigid at the end of the prepupal stage. Thus, a greater force of contraction would be required to elongate the legs and wings to their normal length during the prepupal-pupal transition. Defective cuticle does not explain failed gas bubble translocation, however, so it appears that, in the ßFTZ-F1 mutant, muscle contractions are insufficient. Nonetheless, the notion of increased cuticular rigidity is an interesting concept that merits future exploration (Fortier, 2003).

These findings indicate that the major morphogenetic defects seen in ßFTZ-F1 mutants result from ineffective muscular contractions at the normal time of the prepupal-pupal transition. ßFTZ-F1 regulates the expression of several genes during the late-prepupal stage, including BR-C, E74A, E75A, and E93. The defects seen during pupation in the ßFTZ-F1 mutant are possibly due to the reduced expression of one or more of these, or other, target genes. Attempts will be made to determine which ßFTZ-F1 target genes direct these morphogenetic events. ßFTZ-F1 is ubiquitously expressed in mid-prepupae. Further characterization of this expression pattern will be helpful in understanding the function of ßFTZ-F1 in morphogenesis. As a competence factor that enables genes to respond to ecdysone at the right time in the proper cells, ßFTZ-F1 has a pivotal position in directing the transformation from larva to adult. Elucidating the role of ßFTZ-F1 in Drosophila metamorphosis will be an important step toward understanding how steroid hormones coordinate the complex events of animal development (Fortier, 2003).

Self-digestion of cytoplasmic components is the hallmark of autophagic programmed cell death. This auto-degradation appears to be distinct from what occurs in apoptotic cells that are engulfed and digested by phagocytes. Although much is known about apoptosis, far less is known about the mechanisms that regulate autophagic cell death. Autophagic cell death is regulated by steroid activation of caspases in Drosophila salivary glands. Salivary glands exhibit some morphological changes that are similar to apoptotic cells, including fragmentation of the cytoplasm, but do not appear to use phagocytes in their degradation. Changes in the levels and localization of filamentous Actin, alpha-Tubulin, alpha-Spectrin and nuclear Lamins precede salivary gland destruction, and coincide with increased levels of active Caspase 3 and a cleaved form of nuclear Lamin. Mutations in the steroid-regulated genes ßFTZ-F1, E93, BR-C and E74A that prevent salivary gland cell death possess altered levels and localization of filamentous Actin, alpha-Tubulin, alpha-Spectrin, nuclear Lamins and active Caspase 3. Inhibition of caspases, by expression of either the caspase inhibitor p35 or a dominant-negative form of the initiator caspase Dronc, is sufficient to inhibit salivary gland cell death, and prevent changes in nuclear Lamins and alpha-Tubulin, but not to prevent the reorganization of filamentous Actin. These studies suggest that aspects of the cytoskeleton may be required for changes in dying salivary glands. Furthermore, caspases are not only used during apoptosis, but also function in the regulation of autophagic cell death (Martin, 2004).

Proteolysis and changes in the assembly of the cytoskeleton both appear to be involved in the regulation of changes that occur during autophagic cell death of salivary glands. Although caspases play an important role in the cell death of salivary glands, several lines of evidence suggest that some changes in the structure of the cytoskeleton may occur in a caspase-independent manner. First, whereas changes in filamentous Actin localization occur in synchrony with changes in proteins such as nuclear Lamins that are cleaved by caspases, changes in Actin protein levels are delayed by 4 hours. Second, mutations in steroid-signaling genes, such as ßFTZ-F1, that prevent expression of active caspase-3 and cleavage of nuclear Lamins do not prevent changes in filamentous Actin localization. Third, although inhibition of caspases by expression of either p35 or a dominant-negative form of Dronc is sufficient to prevent changes in nuclear Lamins and alpha-Tubulin, these inhibitors are not sufficient to block changes in filamentous Actin. These data are further supported by the observation that numerous small GTPases increase their expression immediately prior to salivary gland cell death. Although previous studies have suggested that changes in the Actin cytoskeleton are required for autophagic cell death, the failure to distinguish between cytoskeleton proteolysis and rearrangement has made it difficult to interpret the potential significance of maintenance of the cytoskeleton during cell death (Martin, 2004).

Studies of salivary glands indicate that caspases play an important role in their autophagic cell death. The caspase-encoding genes dronc and drice show an increase in their transcription following the rise in steroid that triggers salivary gland autophagic cell death. This increase in caspase transcription corresponds to the increase in active caspase protein levels and in the cleavage of substrates such as nuclear Lamins in dying salivary glands. Mutations in the steroid-regulated ßFTZ-F1, E93 and BR-C genes, which prevent salivary gland cell death, exhibit little or no active Caspase-3/Drice expression, and have altered alpha-Tubulin, alpha-Spectrin and nuclear Lamin expression in salivary glands. Although E74A mutants prevent salivary gland cell death, they have elevated Caspase-3/Drice levels and degraded nuclear Lamins. Although these data are consistent with the partially degraded morphology of E74A mutant salivary glands, it remains unclear what factor(s) E74A may regulate that are required for normal cell death. However, the data indicate that ßFTZ-F1, E93 and BR-C play a crucial role in determining caspase levels in dying salivary gland cells, and this is supported by the impact of these genes on the transcription of dronc. Significantly, inhibition of caspases by expression of either p35 or dominant-negative Dronc is sufficient to prevent DNA fragmentation, changes in nuclear Lamins and alpha-Tubulin, and death of salivary glands (Martin, 2004).

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date revised: 25 June 2007

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