PT  - JOURNAL ARTICLE
AU  - Sabrina Maxeiner
AU  - Judith Grolleman
AU  - Tobias Schmid
AU  - Jan Kammenga
AU  - Alex Hajnal
TI  - The hypoxia-response pathway modulates RAS/MAPK–mediated cell fate decisions in <em>Caenorhabditis elegans</em>
AID  - 10.26508/lsa.201800255
DP  - 2019 Jun 01
TA  - Life Science Alliance
PG  - e201800255
VI  - 2
IP  - 3
4099  - https://www.life-science-alliance.org/content/2/3/e201800255.short
4100  - https://www.life-science-alliance.org/content/2/3/e201800255.full
SO  - Life Sci. Alliance2019 Jun 01; 2
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.