Whole-mount embryonic in situ hybridization experiments using different sima cDNA probes were performed to determine the sima expression pattern. Hybridization was observed in most or all cells from the blastoderm stage through the end of embryogenesis. The significant amounts of sima transcripts in syncitial blastoderm embryos suggest a maternal contribution of sima. The pattern of sima transcripts completely overlaps that of sim and trk (Nambu, 1996).
The Drosophila piwi gene is the founding member of the only known family of genes whose function in stem cell maintenance is highly conserved in both animal and plant kingdoms. piwi mutants fail to maintain germline stem cells in both male and female gonads. The identification of piwi-interacting genes is essential for understanding how stem cell divisions are regulated by piwi-mediated mechanisms. To search for such genes, the Drosophila third chromosome (~36% of the euchromatic genome) was screened for suppressor mutations of piwi2, and six strong and three weak piwi suppressor genes/sequences were identified. These genes/sequences interact negatively with piwi in a dosage-sensitive manner. Two of the strong suppressors represent known genes -- serendipity-delta and similar, both encoding transcription factors. These findings reveal that the genetic regulation of germline stem cell division involves dosage-sensitive mechanisms and that such mechanisms exist at the transcriptional level. In addition, three other types of piwi interactors were identified. The first type consists of deficiencies that dominantly interact with piwi2 to cause male sterility, implying that dosage-sensitive regulation also exists in the male germline. The other two types are deficiencies that cause lethality and female-specific lethality in a piwi2 mutant background, revealing the zygotic function of piwi in somatic development (Smulders-Srinivasan, 2003).
Like Sry-delta, Similar and Tango play a key role in the dosage-sensitive regulation of germline stem cell division. Similar is homologous to a large group of heterodimerizing transcriptional activators. It shows closest homology to the human hypoxia inducible factor-1alpha (HIF-1alpha) and has been shown to function in hypoxic response in Drosophila. HIF-1alpha binds to HIF-1ß to drive transcription of downstream genes. Since Tango is the only Drosophila homolog of HIF-1ß, it is likely to be a partner of Similar. Indeed, Tango interacts with Similar in the yeast two-hybrid system. However, Tango is also known to bind to two other Drosophila bHLH-PAS family proteins, Single-minded and Trachealess, to mediate the transcription of their downstream targets. By showing that tango suppresses the germline stem cell phenotype of piwi2, this study suggests that Tango heterodimerizes with Similar in the dosage-sensitive transcriptional activation of genes involved in germline stem cell division (Smulders-Srinivasan, 2003).
Hypoxia-Inducible Factor (HIF) prolyl hydroxylase domains (PHDs) have been proposed to act as sensors that have an important role in oxygen homeostasis. In the presence of oxygen, they hydroxylate two specific prolyl residues in HIF-alpha polypeptides, thereby promoting their proteasomal degradation. So far, however, the developmental consequences of the inactivation of PHDs in higher metazoans have not been reported. This study describes novel loss-of-function mutants of fatiga (HIF prolyl hydroxylase), the gene encoding the Drosophila PHD oxygen sensor, that manifest growth defects and lethality. A null mutation in dHIF-alpha/similar (sima) is reported, that is unable to adapt to hypoxia but is fully viable in normoxic conditions. Strikingly, loss-of-function mutations of sima rescue the developmental defects observed in fatiga mutants and enable survival to adulthood. These results indicate that the main functions of Fatiga in development, including control of cell size, involve the regulation of dHIF/Sima (Centanin, 2005).
Recent work has led to the definition of widely operative signalling systems that control the transcriptional response to hypoxia through hypoxia-inducible factor (HIF). HIF proteins are a family of alpha/ß-heterodimers in which the common ß-subunit is constitutive and the alpha-subunits are oxygen-regulated by mechanisms that include transcriptional co-activator recruitment, subcellular localization and protein stabilization. The regulation of proteasomal degradation of alpha-subunits has been well characterized in cell culture and in in vitro systems. In the presence of oxygen, a series of 2-oxoglutarate and iron-dependent dioxygenases termed PHDs (prolyl hydroxylase domains) hydroxylate specific prolyl residues in the HIF-alpha oxygen-dependent degradation domain (ODDD), enabling its ubiquitination and proteasomal degradation. As molecular oxygen is absolutely required in the prolyl hydroxylation reaction and enzyme activity is sensitive to mild hypoxia, the PHDs have suitable characteristics that enable them to function as bona fide oxygen sensors that determine the half-life of HIF-alpha proteins, thereby controlling hypoxia-dependent transcription. Analyses of 'knockout' mouse strains have shown developmental roles of mammalian HIF proteins. They are required for the normal formation of the heart, brain, vasculature, cartilage and placenta, suggesting that fetal oxygen availability might have a role in these processes. However, this question remains open, and the developmental effects of genetic inactivation of the oxygen-sensitive PHD pathways have not yet been defined (Centanin, 2005).
The Drosophila bHLH-PAS proteins Similar (Sima) and Tango (Tgo) are, respectively, the functional homologues of HIF-alpha and HIF-ß in the fly. A lethal P-element insertional mutation (l(3)02255) is described in the Drosophila PHD gene (CG1114 in FlyBase) that fails to downregulate Sima protein in normoxia, thus driving constitutive activation of the transcriptional response to hypoxia. The aim of the present work was to investigate the developmental role of Drosophila PHD, which has been termed fatiga (fga; Spanish for 'fatigue') after its lack-of-oxygen phenotype (Centanin, 2005).
As a first step in the study of the functions of fga in development, new loss-of-function mutations were generated by mobilizing the l(3)02255 P-element, which is located between the second and third exons of the fga gene. Precise excisions of the transposon led to a reconstitution of the wild-type hypoxic response, as shown by hypoxia-inducible expression of transcriptional reporters that are based on the murine LDH-A enhancer. Imprecise excisions of the P-element resulted in three novel fga alleles (fga1, fga9 and fga64) that were characterized at the molecular level by Southern blot analysis and PCR experiments. fga9 conserved a 1.4 kb fragment of the original transposon; in fga64, a large genomic portion upstream of the insertion site was removed, and fga1 conserved a fragment of about 9 kb of the original P-element. In normoxic wild-type embryos, Sima protein and induction of the Ldh-Gal4 reporter are not detected; upon exposure to hypoxia (5% O2), both Sima protein and reporter expression are observed, mainly in the tracheal system. The molecular basis of this pattern of induction is now under investigation. Interestingly, fga loss-of-function alleles show different levels of accumulation of Sima protein in normoxia, which was widely expressed in fga1 and fga64, and shows some prevalence in the tracheal system in fga9, correlating with the constitutive induction of the hypoxic reporter. fga02255, fga1 and fga64 are lethal at the first larval instar and fga9 die in the pupal stage. Because overexpression of Sima through a ubiquitous Gal4 driver provokes lethality in the larval stages, it was reasoned that lethality in fga mutants could be due to overaccumulation of Sima protein in normoxia. To test this hypothesis and to determine if Fga is a dedicated regulator of Sima or whether, alternatively, it might modulate other molecular targets, attempts were made to analyse fga phenotypes in a sima-free genetic background. Loss-of-function mutations of sima have not been reported so far, but two different P-element insertions mapping within the sima locus were available from the Public Stock Centers. One of these insertion lines was able to respond to hypoxia and, thus, was indistinguishable from the wild type. In contrast, embryos homozygous for the other insertion, sima07607, did not express sima mRNA and failed to induce the Ldh-LacZ reporter in hypoxia. Introduction of a UAS-Sima transgenic element under the control of an hs-Gal4 driver was able to rescue induction of reporter expression, which was expressed in a wild-type pattern, indicating that the absence of Sima was indeed responsible for the lack of hypoxic response. Altogether, these results indicate that sima07607 is a sima loss-of-function allele (Centanin, 2005).
To explore whether the absence of Sima protein, and thus the inability to respond to hypoxia, affects developmental progression, phenotypes were analysed in sima07607 mutants. Homozygous mutant embryos developed without any obvious difference from the controls, and the first-instar larvae looked healthy and motile. Next, homozygous mutant or control larvae were placed in vials containing fresh food, which were then exposed to 21% or 5% O2 until individuals attained the pupal stage. sima07607 mutants were viable and fertile in normoxia, but virtually unable to develop in hypoxia. Precise excision of the P-element totally reverted hypoxia-dependent lethality, which indicated that the insertion was indeed responsible for this phenotype. Thus, it is concluded that, unlike Tango that participates as a common bHLH-PAS partner in several developmental processes in normoxia, Sima is necessary for developmental progression in hypoxia but not in normoxia (Centanin, 2005).
fga mutations caused a reduction in cell size, but it is unclear whether this effect depends on overaccumulation of Sima. The availability of sima07607 as a sima loss-of-function allele enabled this particular question to be answered and, more generally, the extent to which the developmental defects of fga loss-of-function mutations are due to the de-regulated accumulation of Sima protein to be addressed. As expected, in fga1sima07607 double homozygous mutants, Sima protein is undetectable and embryos do not show any expression of hypoxia-inducible reporters in normoxia. Consistent with previously described growth defects of fga mutants, fga9 pupae are smaller than their heterozygous siblings and, interestingly, they exhibited a delay in larval development, taking 2 additional days to reach the pupariation stage. Strikingly, fga1sima07607 double homozygous mutants are indistinguishable from the controls, both in their pupal weight and in the duration of larval development. Thus, the loss of Sima provokes the complete reversion of growth defects occurring in fga mutants. To answer whether overaccumulation of Sima is sufficient to account for the autonomous reduction in cell size reported for fga mutant cells, Sima protein was overexpressed in random clones using the flipase-induced recombination (FLP-OUT) technique, and the effect on cell size was analysed. Overexpression of Sima in isolated cells causes a marked autonomous reduction of cell size, which correlated with smaller nuclei. Taken together, these results indicate that Sima is a downstream effector of Fga as a regulator of cell growth. Further analyses were carried out on the tracheal system; once again defects (particularly, air-filling impairment) that are observed in fga mutants, are corrected in fga sima double mutants (Centanin, 2005).
Given the reversion of the analysed fga phenotypes in fga sima double mutants, it was of interest to test whether lethality that occurred following fga loss-of-function is also due to overaccumulation of Sima. This is indeed the case, since, in normoxia, fga1 sima07607 double homozygous mutants are viable to adulthood, even when many of these adults fail to complete emergence from the pupal case, and those that emerged looked weak and frequently die shortly afterwards. As expected, in hypoxia, this reversion of lethality does not occur, and fga or sima single mutants, as well as fga sima double mutant flies, die in the first larval stage. Overall, these results show that Drosophila development can proceed in the absence of PHD oxygen sensors, provided that the HIF-alpha subunit is absent and oxygen availability is not compromised. Thus, it is concluded that the most fundamental functions of Fatiga/PHD in development probably involve the downregulation of Sima protein levels. However, fga sima exarate adults show defects in wing and ovary development, which may imply that Fga is involved in patterning these organs in a Sima-independent manner. Detailed genetic and molecular analyses of fga sima double mutants should help to define Sima-independent developmental functions of the oxygen sensor in Drosophila (Centanin, 2005).
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date revised: 17 July 2008
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