A Dominant-Negative HIF-1 Isoform Protects Neuronal Development by Buffering the Response to Hypoxia in C. elegans

Animal cells respond to hypoxic stress through cell-autonomous stabilization of HIF-1, a conserved transcription factor that mediates adaptation to low-oxygen environments. Although HIF-1 is essential for viability under hypoxia, its persistent activation during development causes miswiring defects in the nervous system, raising the question of how developing neurons balance the pro-survival benefits of HIF-1 stabilization against these associated risks. Here we show that C. elegans neurons address this challenge by mobilizing an internal promoter within the hif-1 locus to generate a dominant-negative isoform, HIF-1c, which acts in the nucleus to limit HIF-1/AHA-1 heterodimer formation. This buffering mechanism supports proper neuronal migration, axon guidance, and circuit formation and its loss phenocopies the defects seen when the ubiquitous HIF-1 degradation pathway is disrupted, confirming that HIF-1c serves as a critical layer of protection for the developing nervous system against hypoxic-induced errors. Lastly, we identify the retinoblastoma protein LIN-35 as a modulator of HIF-1 signaling in worms via control of hif-1c expression.