Drosophila dMRP4 regulates responsiveness to O2 deprivation and development under hypoxia

For most vertebrates, oxygen is a prerequisite for survival. Although we have previously shown that Drosophila melanogaster is hypoxia tolerant, how this species senses O(2) deprivation and how it survives oxygen-limiting conditions are as yet poorly understood. We began to address this question by testing for anoxic responsiveness in Drosophila adult flies following overexpression of existing EP lines. In this screen, we identified Drosophila CG14709 gene as a homolog of the human multidrug resistance protein 4 (MRP4/ABCC4) that is tightly regulated to oxygen. Ubiquitous expression of dMRP4 in adult flies resulted in increased sensitivity to anoxia as they had longer recovery time from anoxic stupor. When exposed to 4% oxygen chronically (throughout its lifespan), constitutive expression of dMRP4 in larvae caused larval lethality due to growth arrest. Mutations of dMRP4 led to a hypersensitive response to acute anoxia in adult flies but had less impact on larval survival under chronic hypoxia compared with dMRP4 overexpression. Selective expression of this gene in neurons, but not in glia or muscles, mirrored the same phenotype as the ubiquitous one. Thus, our data suggest novel roles for MRP in vivo: 1) dMRP4 regulates the sensitivity to acute or chronic O(2) deprivation, and 2) dMRP expression in neurons is sufficient to induce the sensitivity to O(2) in the whole organism.