Notch Signaling and Cross-Talk in Hypoxia: A Candidate Pathway for High-Altitude Adaptation

Abstract

Hypoxia triggers complex inter- and intracellular signals that regulate tissue oxygen (O₂) homeostasis, adjusting convective O₂ delivery and utilization (i.e., metabolism). Human populations have been exposed to high-altitude hypoxia for thousands of years and, in doing so, have undergone natural selection of multiple gene regions supporting adaptive traits. Some of the strongest selection signals identified in highland populations emanate from hypoxia-inducible factor (HIF) pathway genes. The HIF pathway is a master regulator of the cellular hypoxic response, but it is not the only regulatory pathway under positive selection. For instance, regions linked to the highly conserved Notch signaling pathway are also top targets, and this pathway is likely to play essential roles that confer hypoxia tolerance. Here, we explored the importance of the Notch pathway in mediating the cellular hypoxic response. We assessed transcriptional regulation of the Notch pathway, including close cross-talk with HIF signaling, and its involvement in the mediation of angiogenesis, cellular metabolism, inflammation, and oxidative stress, relating these functions to generational hypoxia adaptation.

Keywords: Notch signaling; adaptation; hypobaric hypoxia; hypoxia-inducible factor.

Figure 1

A simplified view of canonical Notch signaling. Summary of the core signaling pathway created with BioRender.com. Canonical Notch ligands bind to the Notch receptors at epidermal growth factor (EGF) repeats 11–12 (dark green sections). Cleavage of the Notch receptor involves two proteolytic cleavage events, the first catalyzed by ADAM metalloproteases at the negative regulatory region (purple sections), the second by γ-secretase. This releases the Notch intracellular domain (NICD). In the nucleus, NICD interacts with DNA binding protein CBF1/Suppressor of Hairless/LAG1 (CSL; also known as RBPJ) and the coactivator Mastermind (MAM) to promote gene transcription.