Evolutionarily Conserved Notch‐Dependent and Independent Mechanisms Regulating Hypoxia Tolerance

Abstract

Hypoxia tolerance is an important trait for human populations living at high altitude. It is also clinically important for patients suffering from illnesses in which hypoxia represents a critical element in the pathogenesis, such as ischemic stroke, myocardial infarction and solid tumors. Our previous studies and those of others have shown that the mechanisms underlying hypoxia tolerance are polygenic and evolutionarily conserved. Indeed, we and others have found that Notch signaling regulates hypoxia tolerance in both Drosophila melanogaster and humans. However, the mechanistic details underlying Notch‐conferred hypoxia tolerance are largely unknown. By comparing candidate genes identified through whole genome sequencing analysis of hypoxia‐adapted fruit flies and those from genome‐wide single nucleotide polymorphism data from four high‐altitude human populations (i.e., Sherpas, Tibetans, Ethiopians and Andeans), we have identified several, evolutionary conserved genes involved in hypoxia tolerance. In the current study, we developed a novel dual‐USA/Gal4 system to determine genetic interactions between Notch signaling and these conserved genes in terms of hypoxia tolerance. This unique system allows us to activate Notch signaling in the Eaat1 positive cells, which dramatically enhances hypoxia tolerance in flies, and, simultaneously, knockdown a candidate gene in the same glial cells. Using this system, we discovered that Notch‐conferred hypoxia tolerance requires HES1/hairy, FOXC1/croc and ZNF521/Oaz. In contrast, KCND2/Shal and EGFR/Egfr regulate hypoxia tolerance in a Notch‐independent manner. Furthermore, Notch activation can partially rescue lethality under hypoxic condition with FGF/bnl down regulation. In summary, we identified evolutionarily conserved, Notch‐dependent and independent mechanisms regulating hypoxia tolerance. These mechanisms have strong potential to be translated into humans and serve as novel targets for developing therapeutic strategies to treat hypoxia‐related diseases.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.