Cellular and Developmental adaptations to hypoxia; a Drosophila perspective.

ROMERO N.M.; DEKANTY A.; WAPPNER P.

METHODS IN ENZYMOLOGY.

Elsevier

Año: 2007 vol. 435 p. 123 - 144

0076-6879

The fruit fly Drosophila melanogaster, a widely utilized genetic model, is highly resistant to oxygen starvation and is beginning to be used for studying physiological, developmental and cellular adaptations to hypoxia. The Drosophila respiratory (tracheal) system has features in common with the mammalian circulatory system, so that an angiogenesis-like response occurs upon exposure of Drosophila larvae to hypoxia. A hypoxia-responsive system homologous to mammalian HIF has been described in the fruit fly, where Fatiga is a Drosophila oxygen-dependent HIF prolyl hydroxylase, and the bHLH-PAS proteins Sima and Tango are respectively the Drosophila homologues of mammalian HIF-a and HIF-b. Tango is constitutively expressed regardless of oxygen tension and like in mammalian cells, Sima is controlled at the level of protein degradation and subcellular localization. Sima is critically required for development in hypoxia but unlike mammalian model systems, it is dispensable for development in normoxia. In contrast, fatiga mutant alleles are all lethal, but strikingly, viability to adulthood is restored in fatiga sima double mutants, although these double mutants are not entirely normal, suggesting that Fatiga has Sima-independent functions in fly development. Studies in cell culture and in vivo have revealed that Sima is activated by the insulin receptor (InR) and TOR pathways but paradoxically, Sima is a negative regulator of growth. This suggests that Sima is engaged in a negative feed-back loop that limits growth upon stimulation of InR/TOR pathways.