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).

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).

The Drosophila nuclear receptors DHR3 and βFTZ-F1 control overlapping developmental responses in late embryos

Studies of the onset of metamorphosis have identified an ecdysone-triggered transcriptional cascade that consists of the sequential expression of the transcription-factor-encoding genes DHR3, βFTZ-F1, E74A and E75A. Although the regulatory interactions between these genes have been well characterized by genetic and molecular studies over the past 20 years, their developmental functions have remained more poorly understood. In addition, a transcriptional sequence similar to that observed in prepupae is repeated before each developmental transition in the life cycle, including mid-embryogenesis and the larval molts. Whether the regulatory interactions between DHR3, βFTZ-F1, E74A and E75A at these earlier stages are similar to those defined at the onset of metamorphosis, however, is unknown. This study turned to embryonic development to address these two issues. It was shown that mid-embryonic expression of DHR3 and βFTZ-F1 is part of a 20-hydroxyecdysone (20E)-triggered transcriptional cascade similar to that seen in mid-prepupae, directing maximal expression of E74A and E75A during late embryogenesis. In addition, DHR3 andβFTZ-F1 exert overlapping developmental functions at the end of embryogenesis. Both genes are required for tracheal air filling, whereas DHR3 is required for ventral nerve cord condensation and βFTZ-F1 is required for proper maturation of the cuticular denticles. Rescue experiments support these observations, indicating that DHR3 has essential functions independent from those of βFTZ-F1. DHR3 and βFTZ-F1 also contribute to overlapping transcriptional responses during embryogenesis. Taken together, these studies define the lethal phenotypes of DHR3 and βFTZ-F1 mutants, and provide evidence for functional bifurcation in the 20E-responsive transcriptional cascade (Ruaud, 2010).

The regulatory interactions between DHR3, αFTZ-F1 and E74A/E75A that are described in this study in embryos are indistinguishable from those seen in prepupae. First, DHR3 expression in embryos is dependent on 20E signaling. Second, DHR3 mutants display reduced levels of αFTZ-F1, E74A and E75A expression at both stages in the life cycle, and αFTZ-F1 mutants have reduced levels of E74A mRNA and no detectable E75A expression. Taken together with studies that show that ectopic αFTZ-F1 is sufficient to drive maximal expression of E74A and E75A, these results indicate that DHR3 exerts its effect on these genes through its induction of αFTZ-F1 in embryos. Third, a loss of DHR3 function during embryogenesis does not eliminate αFTZ-F1 expression. This is probably due to other upstream factors that contribute to this response. One candidate for this function is the DHR4 nuclear receptor, which is coexpressed with DHR3 in both embryos and prepupae. DHR4 mutants have no effect on DHR3 expression, but display significantly reduced levels of αFTZ-F1 mRNA in prepupae. These mutants, however, have no effect on embryonic development, suggesting that DHR4 does not play a major role in αFTZ-F1 induction at this early stage in the life cycle (Ruaud, 2010).

The late larval pulse of 20E both directly and indirectly induces DHR3 and represses αFTZ-F1. Taken together with the inductive effect of DHR3 on αFTZ-F1 expression, this regulation ensures that the peak of αFTZ-F1 expression will be delayed until the proper time during development. The observation that the embryonic 20E pulse, at ~8 hours AEL, immediately precedes DHR3 expression suggests that similar regulatory interactions are acting in embryos. However, unlike prepupae, there is no known hormone peak in late embryos that could account for the coordinated induction of E74A and E75A mRNA at this time, as is known to occur in late prepupae. It is possible that these transcripts are fully dependent on trans-acting factors such as αFTZ-F1 for their expression in embryos. Alternatively, these 20E primary-response genes might be induced by a novel temporal signal that remains to be identified (Ruaud, 2010).

It is interesting to note that a similar temporal profile of DHR3, αFTZ-F1 and E74A/E75A expression is also seen in larvae. A burst of DHR3 expression in mid-second instar larvae immediately follows the peak in the 20E titer and precedes the transient expression of αFTZ-F1, which is followed by co-expression of E74A and E75A at the end of the instar. Curiously, E75A, but not E74A, is expressed at an earlier time as well, in apparent synchrony with the 20E pulse, recapitulating the timing seen in embryos. It is thus likely that a common set of regulatory interactions function in both embryos and larvae to dictate the precise timing of these expression patterns at each stage in the life cycle, prior to the third instar. Moreover, the observation that EcR, E75A and αFTZ-F1 mutants display defects in larval molting indicates that their expression is essential for proper progression through these stages in development (Ruaud, 2010).

DHR3 and αFTZ-F1 null mutations lead to fully penetrant embryonic lethality, with relatively minor and partially penetrant phenotypes reported in DHR3 mutant embryos and no phenotypic description of αFTZ-F1 mutant embryos. The studies described in this paper define both common and unique functions for these two nuclear receptors during embryogenesis. DHR3 and αFTZ-F1 null mutants both display a highly penetrant defect in air filling of the tracheal tree. In addition to this common function, αFTZ-F1 is required for the proper differentiation of the denticles in the ventral cuticle and DHR3 is required for VNC condensation. Both DHR3 and αFTZ-F1 mutants display apparently normal muscle movements at the end of embryogenesis, indicating that only some developmental responses are blocked at this stage. These processes of cuticle differentiation, tracheal air filling, muscular movements and VNC condensation represent the major developmental events that can be described in late embryos. Defects in three of these four pathways thus define a central role for DHR3 and αFTZ-F1 in late embryonic development. In addition, unlike prepupae, in which DHR3 and αFTZ-F1 mutants have essentially identical phenotypes, these studies establish independent functions for these two nuclear receptors during development. Together with the previously identified early embryonic roles of the 20E receptor EcR in dorsal closure, head involution and midgut morphogenesis, these data indicate that each step of the 20E-induced transcriptional cascade controls sequential developmental programs during embryogenesis. Moreover, the observation that this transcriptional cascade is also required for larval molting suggests that it represents a stereotypic 20E response that is required for progression through each major transition in the life cycle (Ruaud, 2010).

Ectopic expression of wild-type αFTZ-F1 is sufficient to rescue the lethality of αFTZ-F1 mutants, but has no effect on the viability of DHR3 mutants, indicating that DHR3 exerts essential functions independently of its downstream partner. The causes of lethality in DHR3 and αFTZ-F1 mutant embryos, however, remain unclear. Strong loss-of-function mutations in the signal peptide peptidase (Spp) gene result in tracheal air-filling defects; however, Spp mutant embryos hatch normally and die as first or second instar larvae. Similarly, embryos with severe defects in VNC condensation can hatch into first instar larvae and survive to later stages of development. These results indicate that the lethality of DHR3 and αFTZ-F1 mutant embryos cannot be directly attributed to defects in these pathways. Rather, DHR3 and αFTZ-F1 may participate in a developmental checkpoint necessary to trigger the last steps of embryogenesis required for hatching and survival (Ruaud, 2010).

The microarray study revealed that a number of 20E-responsive genes are misregulated in DHR3 mutants, consistent with studies in prepupae that indicate a crucial role for DHR3 in 20E signaling. The microarray analysis also identified several genes that are involved in chitin metabolism and protein secretion, which could account for the defects in tracheal gas filling seen in DHR3 mutants. These included the chitinase genes Idgf5 (-8.6-fold) and kkv (+2.4-fold), the CBP Cht12 (+2.6-fold) and the COPII coat subunit sec13 (+2.5-fold). This study also identified a number of genes that play a role in axon guidance. Interestingly, most of these genes have dose-dependent effects, whereby either reduced or increased expression can disrupt nervous system development. Failure of DHR3 mutant embryos to express these genes at normal levels could thus contribute to the PNS defects (Ruaud, 2010).

Northern blot hybridization studies to examine the effects of DHR3 and αFTZ-F1 mutants on selected DHR3-regulated genes confirm and extend phenotypic studies of these mutants. Some genes, such as retn, E93 and kkv, display similar transcriptional responses in DHR3 and αFTZ-F1 mutants, whereas E74A and E75A are more significantly affected in αFTZ-F1 mutants and Idgf5 is selectively reduced in DHR3 mutants. These transcriptional effects support phenotypic studies and provide further evidence that DHR3 and αFTZ-F1 exert common and independent regulatory roles during embryogenesis. This conclusion is consistent with experimental and theoretical studies of gene regulatory networks, which indicate that transcriptional cascades provide an effective means of amplifying signals and integrating multiple cues to provide specificity in biological responses. Transcriptional cascades can also direct temporal programs of successive gene expression, as observed in the formation of flagella in Escherichia coli and the specification of anteroposterior patterning in the Drosophila embryo. In addition, the DHR3-αFTZ-F1 transcriptional cascade involves nuclear receptors that could potentially act as ligand-regulated transcription factors, introducing an additional level of control by small lipophilic compounds. These observations support the proposal that the sequential expression of DHR3 and αFTZ-F1 at multiple stages of development can specify successive biological programs that promote appropriate progression through the life cycle. By combining insect endocrinology with the predictive power of genetics, the 20E-triggered transcriptional cascades in Drosophila provide an ideal context to define how a repeated systemic signal can be refined into precise stage-specific temporal responses during development (Ruaud, 2010).

DHR3 is required for VNC condensation, a terminal step in embryonic nervous system morphogenesis that is dependent on nervous system activity, glial cell function and apoptosis. In addition, previous studies have identified roles for DHR3 in PNS development. Interestingly, these functions, which are specific for DHR3 and are not shared with its direct target, αFTZ-F1, parallel the role of the mammalian DHR3 homolog RORα in brain development. RORα was initially identified as the gene associated with the spontaneous staggerer mutation in mice, which display ataxia associated with cerebellum developmental defects and degeneration. The cerebellum in staggerer mutants is dramatically smaller than in controls, containing fewer of the two major cell types: granule cells and Purkinje cells. Further investigation showed that this phenotype arises primarily from reduced expression in Purkinje cells of Sonic hedgehog (Shh), a mitogenic signal for granule cells. These data support the hypothesis that there is an evolutionarily conserved role for the ROR/DHR3 family of nuclear receptors in nervous system development and suggest that further functional studies of DHR3 may provide new insights into its ancestral functions in this pathway (Ruaud, 2010).

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date revised: 15 December 2011

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