Abstract
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.
Highlights
The RAS/MAPK pathway regulates cell growth, differentiation, proliferation, apoptosis, and migration in all metazoans (Simanshu et al, 2017)
Strong activation of the RAS/MAPK signaling pathway in P6.p, the vulval precursor cells (VPCs) located closest to the anchor cell (AC), induces the primary (1°) cell fate and up-regulates the expression of DELTA-like DSL ligands, which activate lateral NOTCH signaling in the adjacent VPCs (Chen & Greenwald, 2004)
The two polymorphic genes F44F1.1 and pfd-3 have previously been found to modify RAS/MAPK signaling during vulval development and to suppress the egg-laying–defective phenotype of egl-9(lf) mutants (Gort et al, 2007; Schmid et al, 2015)
Summary
The RAS/MAPK pathway regulates cell growth, differentiation, proliferation, apoptosis, and migration in all metazoans (Simanshu et al, 2017). An EGF-like ligand (LIN-3) secreted by the gonadal anchor cell (AC) activates EGFR/RAS/MAPK signaling in the adjacent vulval precursor cells (VPCs) through the EGF receptor (LET-23) pathway (Fig 1A). Strong activation of the RAS/MAPK signaling pathway in P6.p, the VPC located closest to the AC, induces the primary (1°) cell fate and up-regulates the expression of DELTA-like DSL ligands, which activate lateral NOTCH signaling in the adjacent VPCs (Chen & Greenwald, 2004). The distal VPCs (P3-4.p and P8.p) that receive neither the EGFR/RAS/MAPK nor NOTCH signal adopt the tertiary (3°), uninduced fate. Activating (gain-of-function) mutations in the RAS/MAPK pathway lead to the ectopic induction of distal VPCs and a multivulva (Muv) phenotype, whereas loss-of-function mutations in RAS/MAPK pathway components cause a vulvaless (Vul) phenotype.
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