LAUSR

ABSTRACT Inadequate delivery of oxygen to organisms during development can lead to cell dysfunction/death and life‐long disabilities. Although the susceptibility of developing cells to low oxygen conditions changes with maturation, the cellular and molecular pathways that govern responses to low oxygen are incompletely understood. Here we show that developing Caenorhabditis elegans are substantially more sensitive to anoxia than adult animals and that this sensitivity is controlled by nervous system generated hormones (e.g., neuropeptides). A screen of neuropeptide genes identified and validated nlp‐40 and its receptor aex‐2 as a key regulator of anoxic survival in developing worms. The survival‐promoting action of impaired neuropeptide signaling does not rely on five known stress resistance pathways and is specific to anoxic insult. Together, these data highlight a novel cell non‐autonomous pathway that regulates the susceptibility of developing organisms to anoxia. Graphical abstract Figure. No Caption available. HighlightsDeveloping C. elegans lacking neuropeptide signaling survive anoxic stress better.This effect does not rely on canonical stress resistance pathways.Neurons, not other tissues, are the source of the neuropeptides underlying survival.We employed a directed screen of worm neuropeptides to identify candidates.The screen suggests nlp‐40 partially accounts for anoxic survival phenotype.