Abstract
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. Here, we describe novel loss-of-function mutants of fatiga, the gene encoding the Drosophila PHD oxygen sensor, which manifest growth defects and lethality. We also report a null mutation in dHIF-alpha/sima, which is unable to adapt to hypoxia but is fully viable in normoxic conditions. Strikingly, loss-of-function mutations of sima rescued the developmental defects observed in fatiga mutants and enabled 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.
Highlights
Recent work has led to the definition of widely operative signalling systems that control the transcriptional response to hypoxia through hypoxia-inducible factor (HIF; Maxwell et al, 1993; Wang & Semenza, 1993)
As molecular oxygen is absolutely required in the prolyl hydroxylation reaction and enzyme activity is sensitive to mild hypoxia, the prolyl hydroxylase domains (PHDs) have suitable characteristics that enable them to function as bona fide oxygen sensors that determine the half-life of Hypoxia-Inducible Factor (HIF)-a proteins (Semenza, 2001), thereby controlling hypoxia-dependent transcription
We have previously reported that the Drosophila bHLH-PAS proteins Similar (Sima) and Tango (Tgo) are, respectively, the functional homologues of HIF-a and HIF-b in the fly (Lavista-Llanos et al, 2002; Gorr et al, 2004)
Summary
Recent work has led to the definition of widely operative signalling systems that control the transcriptional response to hypoxia through hypoxia-inducible factor (HIF; Maxwell et al, 1993; Wang & Semenza, 1993). Analyses of ‘knockout’ mouse strains have shown developmental roles of mammalian HIF proteins (Iyer et al, 1998; Adelman et al, 2000; Tomita et al, 2003; Covello & Simon, 2004; Pfander et al, 2004) 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. This question remains open, and the developmental effects of genetic inactivation of the oxygen-sensitive PHD pathways have not yet been defined (Pugh & Ratcliffe, 2003)
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