View Program - 63rd Annual Drosophila Research Conference

When exposed to low oxygen (hypoxia), Drosophila larvae can survive by reducing their growth rate and delaying development to the pupal stage. While the mechanisms that mediate reduced growth have been described, it is less clear how hypoxia delays maturation from the larval to pupal stage. This maturation is controlled by a neuroendocrine circuit in which neuronal projections from the brain innervate the prothoracic gland (PG), an endocrine organ that produces the steroid hormone ecdysone. Activation of this circuit at the end of the larval period triggers a pulse of ecdysone to initiate maturation. We find that larvae reared in hypoxia (5% oxygen) from hatching show delayed ecdysone production (as evidenced by delayed induction of ecdysone biosynthetic genes) resulting in a ~2-day delay in larval maturation. Although hypoxic larvae are delayed in their attainment of critical weight (CW), switching larvae to hypoxia after the CW checkpoint still led to a strong developmental delay, suggesting that hypoxia can specifically act on the larval-to-pupal transition. Interestingly, our data suggest that the developmental delay seems to be independent of the classic hypoxia regulator, HIF-1α and nutrient/TOR signaling. Instead, we find a role for alteration of Ras/MAPK signaling. Expression of ecdysone biosynthetic genes, and thus ecdysone production, is controlled by the conserved Ras/MAPK signaling pathway. PG-specific activation of this pathway is sufficient to reverse the hypoxia-induced developmental delay. Upstream of this MAP kinase pathway in the PG are multiple receptor tyrosine kinases (RTKs). One of these - Epidermal Growth Factor Receptor (Egfr) - has been reported as a major controller of ecdysone production at the end of the larval period. PG-specific RNAi-mediated knockdown of Egfr causes a marked developmental delay. In hypoxic larvae, however, Egfr knockdown in the PG does not delay development any more than hypoxia alone, suggesting that hypoxia and Egfr-knockdown are working in the same pathway. Moreover, Egf ligands, spitz and vein, which mediate autocrine Egfr signaling in the PG, show a delayed induction in hypoxic larvae. We thus find that the post-CW maturation defect in hypoxia may involve suppressed Egfr/Ras signaling in the PG. Owing to conservation in key aspects of steroid hormone regulation, this work adds to our understanding of whole-body responses to hypoxia during development.

Hypoxia-dependent Control of Larval Maturation