Role of 2-Oxoglutarate-dependent di-oxigenases in Drosophila development

JULIETA M. ACEVEDO; MAXIMILIANO JAVIER KATZ; PABLO WAPPNER

San Luis

Congreso; 47th Annual meeting- Argentine Society for Biochemistry and Molecular Biology Research; 2011

Sociedad Argentina de Investigación Bioquímica y Biología Molecular

The Hypoxia Inducible Factor (HIF), is a heterodimeric a/b transcription factor composed of two bHLH-PAS subunits that regulates the response to hypoxia. 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. sima mutants are fully viable and fertile in normoxia and fga mutants are lethal at different developmental stages. 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. 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.