RT Journal Article SR Electronic T1 The hypoxia-response pathway modulates RAS/MAPK–mediated cell fate decisions in Caenorhabditis elegans JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201800255 DO 10.26508/lsa.201800255 VO 2 IS 3 A1 Sabrina Maxeiner A1 Judith Grolleman A1 Tobias Schmid A1 Jan Kammenga A1 Alex Hajnal YR 2019 UL https://www.life-science-alliance.org/content/2/3/e201800255.abstract AB Animals need to adjust many cellular functions to oxygen availability to adapt to changing environmental conditions. We have used the nematode Caenorhabditis elegans as a model to investigate how variations in oxygen concentrations affect cell fate specification during development. Here, we show that several processes controlled by the conserved RTK/RAS/MAPK pathway are sensitive to changes in the atmospheric oxygen concentration. In the vulval precursor cells (VPCs), the hypoxia-inducible factor HIF-1 activates the expression of the nuclear hormone receptor NHR-57 to counteract RAS/MAPK–induced differentiation. Furthermore, cross-talk between the NOTCH and hypoxia-response pathways modulates the capability of the VPCs to respond to RAS/MAPK signaling. Lateral NOTCH signaling positively regulates the prolyl hydroxylase EGL-9, which promotes HIF-1 degradation in uncommitted VPCs and permits RAS/MAPK–induced differentiation. By inducing DELTA family NOTCH ligands, RAS/MAPK signaling creates a positive feedback loop that represses HIF-1 and NHR-57 expression in the proximal VPCs and keeps them capable of differentiating. This regulatory network formed by the NOTCH, hypoxia, and RAS/MAPK pathways may allow the animals to adapt developmental processes to variations in oxygen concentration.