Evolutionarily conserved mechanisms regulating hypoxia tolerance in Drosophila melanogaster

Abstract

Hypoxia is one of the critical pathological elements in many human diseases, including ischemic stroke, myocardial infarction and solid tumors. Understanding the mechanisms regulating hypoxia tolerance or susceptibility is essential for developing effective strategies for medical therapy. In this regard, we generated hypoxia-tolerant Drosophila melanogaster populations through experimental hypoxia-directed evolution in the laboratory, sequenced and analyzed their genomes. In parallel, we took advantage of the natural evolution of humans at high-altitude regions and analyzed the whole genomes of Ethiopian and Andean highlanders. Through a comparative genomic approach, we obtained a group of evolutionarily conserved genes (28 human/23 Drosophila genes) that are potentially involved in regulating hypoxia tolerance in both human highlanders and the hypoxia-tolerant flies. We confirmed that ubiquitous knocking down of the conserved genes, such as grn/ GATA3, inv/ EN1, Mkk4/MAP2K4, Pxt/DUOX1/DUOX2, pyd/TJP1, RapGAP1/RAP1GAP2, Shal/KCN and shep/RBMS3 dramatically enhanced hypoxia tolerance in vivo in Drosophila melanogaster. In addition, we found that glial-specific knocking down of Egfr, grn, pyd and Shal rescued hypoxia-induced lethality. Furthermore, we found that some of these conserved genes (i.e., bnl, croc, Mkk4 and shep) are required by Notch activation-conferred survival in hypoxic environment, whereas Egfr, grn, pyd and Shal regulating hypoxia tolerance through Notch-independent mechanisms. We believe that these evolutionarily conserved mechanisms are novel targets that have a strong potential to be translated into therapeutic strategies to treat or prevent hypoxia-related diseases. This project is supported by NIH grant 1R21NS120023-01A1. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.