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.

中文翻译：

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缺氧反应途径调节秀丽隐杆线虫中RAS / MAPK介导的细胞命运决定。

动物需要调整许多细胞功能以适应氧气供应，以适应不断变化的环境条件。我们使用了线虫秀丽隐杆线虫作为研究氧浓度变化如何影响发育过程中细胞命运指标的模型。在这里，我们显示了由保守的RTK / RAS / MAPK途径控制的几个过程对大气氧浓度的变化敏感。在外阴前体细胞（VPC）中，缺氧诱导因子HIF-1激活核激素受体NHR-57的表达以抵消RAS / MAPK诱导的分化。此外，NOTCH和缺氧反应途径之间的串扰调节了VPC响应RAS / MAPK信号传导的能力。横向NOTCH信号可正向调节脯氨酰羟化酶EGL-9，从而促进未承诺VPC中的HIF-1降解，并允许RAS / MAPK诱导的分化。通过诱导DELTA家族的NOTCH配体，RAS / MAPK信号产生了一个正反馈回路，该回路抑制了近端VPC中的HIF-1和NHR-57表达，并使它们能够区分。由NOTCH，缺氧和RAS / MAPK途径形成的调节网络可能使动物适应发育过程以适应氧浓度的变化。