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. |