Molecular Characterization and Developmental Role of the Drosophila Oxygen Sensor Fatiga

L. Centanin, J.A. Mondotte, P. Wappner. Fundación Instituto Leloir, Universidad de Buenos Aires, Buenos Aires, Argentina.

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric α/ β transcription factor conserved from C. elegans to humans that controls the pleiotropic response to hypoxia. Under normoxic conditions HIF-1 α subunit is rapidly destroyed by a mechanism involving hydroxylation of key proline residues by a novel family of oxygen-dependent prolyl hydroxylases. Hydroxylated prolines can be recognized by the von Hippel Lindau protein, that is part of an E3 ubiquitin ligase complex targeting HIF-1 α for proteasomal destruction. We have demonstrated the occurrence of an homologous hypoxia responsive pathway in Drosophila melanogaster, being Similar (Sima) the HIF-1 α homologue and Fatiga (Fga) the prolyl hydroxylase acting as an oxygen sensor. We have found that disruption of the fga gene results in stabilization of Sima protein and upregulation of the transcriptional response to hypoxia in vivo. We identified three different fga transcripts (fgaA, B, C) that are differentially regulated by oxygen levels: fgaB and C but not fgaA are upregulated in hypoxia and induced upon Sima ectopic expression. We have generated novel fga excision alleles that exhibited alteration in tracheal development, mostly in the fusion pattern of the dorsal branches. Those mutants also exhibited failure in tracheal lumen clearance: first instar mutant larvae showed liquid-filled tracheae instead of wild type air-filled tracheae. Both, fusion pattern and liquid clearance defects were also observed in individuals grown at low oxygen levels or upon ectopic expression of Sima, suggesting that the oxygen sensing machinery modulates the early hard wired tracheal development.

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