Function of the oxygen sensor Fatiga in oogenesis

JULIETA M. ACEVEDO; PABLO WAPPNER

Lisboa

Congreso; 22nd Drosophila Research Conference; 2011

Drosophila research Conference

In response to hypoxia cells, tissues and whole organisms induce the expression of a wide range of genes that tend to restore energy homeostasis. Hypoxic gene induction is mainly mediated by the Hypoxia Inducible Factor (HIF), a heterodimeric a/b transcription factor composed of two bHLH-PAS subunits. While HIF-b is constitutively expressed,  HIF-a subunit is tightly regulated by oxygen. Oxygen regulation is mediated by specific Prolyl-4-hydroxilases (PHDs) that hydroxylate HIF-a in two proline residues utilizing O2 as a co substrate of the reaction. Hydroxylated HIF-a is targeted for degradation at the 26S proteasome. In our lab we have identified Sima and Fatiga (Fga) as the HIF-a and PHD fly homologues respectively. We have shown that whereas sima mutants are fully viable and fertile in normoxia, fga mutants are lethal at different developmental stages. We found that fga lethality is due to Sima over accumulation as fga-sima duble mutants recover viability. Despite being fully viable, fga-sima double mutants are sterile indicating that an alternative Fga target, different from sima, is involved in the Drosophila ovary development. Mutant follicles of fga-sima females are unable to carry out the transition from polyteny to poliploidy that occurs during normal Drosophila oogenesis. We found that Fga is required in the germline but not in follicle cells for oogenesis progression. Over-activation of the transcription factor FOXO in germ cells accounts for the ovary phenotype of the fga sima double mutants, since in fga-sima-foxo triple mutant ovaries were totally normal. Our results therefore suggest that FOXO is negatively regulated by Fga in the germilne, thereby allowing oogenesis progression.