Response to changes in levels of O2 is a fundamental process in human physiology and plays a major role in pathologies as diverse as cardiovascular disease, stroke and cancer. More generally, the capacity to respond to fluctuations in O2 provides an important physiological adaptation for many organisms, including C. elegans. Diminished access to O2 can elicit metabolic, developmental and behavioral responses. Upon exposure to hypoxic conditions (0.5% O2), worms decrease their egg-laying rate (Miller and Roth 2009). We are using the egg-laying behavior of C. elegans as a model for studying behavioral responses to decreased O2 concentrations and for revealing novel aspects of the molecular genetic pathway that functions in response to hypoxia. The prolyl hydroxylase EGL-9 is a key component of the evolutionarily conserved molecular pathway that responds to hypoxia. Our laboratory discovered egl-9 many years ago in a C. elegans screen for mutants defective in egg laying. EGL-9 defines a conserved family of enzymes that hydroxylate the transcription factor hypoxia-inducible factor (HIF-1) using available O2, thus targeting HIF-1 for degradation. Increase in HIF-1 activity as a result of reduced inhibition by EGL-9 under hypoxic conditions is the basis for many C. elegans adaptations to hypoxia, including metabolic and behavioral changes. hif-1(lf) mutations suppress the egg-laying defect of egl-9(lf) mutants. Thus, it is likely that the inhibition of egg laying under hypoxia is controlled by the egl-9/hif-1 pathway. To find downstream effectors of HIF-1 or pathways that regulate egg laying in parallel to HIF-1, we are screening for mutations that suppress the egg-laying defect of egl-9 mutants. We identified an allele of the cytochrome P450 gene cyp-36A1 as a recessive suppressor of the egl-9 egg-laying defect. Previous work has shown that cyp-36A1 is upregulated in hypoxia in a hif-1-dependent manner and contains the putative HIF-1 binding motif in its promoter, suggesting that cyp-36A1 might be a direct transcriptional target of HIF-1 (Shen et al. 2005). Interestingly, another cytochrome P450 gene, cyp-13A12, was identified in our laboratory as acting downstream of egl-9 in the O2-ON locomotory response to changing oxygen levels. CYP-13A12 functions in the generation of an eicosanoid and is downregulated upon hypoxia exposure or in egl-9 mutants (Ma et al. 2013). By contrast, our data indicate that CYP-36A1 generates a hormone that activates a nuclear receptor, and that this pathway is upregulated in egl-9 mutants. We suggest that different cytochrome P450 enzymes act broadly, through multiple mechanisms, downstream of the EGL-9 and HIF-1 in response to alterations in O2 concentrations.
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