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EMBO reports 6, 11, 1070–1075 (2005)
doi:10.1038/sj.embor.7400528
AOP Published online: 23 September 2005
Reversion of lethality and growth defects in Fatiga oxygen-sensor mutant flies by loss of Hypoxia-Inducible Factor- /Sima
Lázaro Centanin1, Peter J Ratcliffe2 & Pablo Wappner1
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1 Instituto Leloir and IIB, FCEyN-Universidad de Buenos Aires, CONICET, Patricias Argentinas 435, Buenos Aires 1405, Argentina
2 The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford OX3 7BN, UK
To whom correspondence should be addressed
Pablo Wappner Tel: +54 11 5238 7500 ext.3112; Fax: +54 11 5238 7501; E-mail: pwappner@leloir.org.ar
Received 29 March 2005; Accepted 12 August 2005; Published online 23 September 2005.
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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- 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-/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.
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