Genetic interactions regulate hypoxia tolerance conferred by activating Notch in excitatory amino acid transporter 1-positive glial cells inDrosophila melanogaster

Abstract

Hypoxia is a critical pathological element in many human diseases, including ischemic stroke, myocardial infarction and solid tumors. Of particular significance and interest of ours are the cellular and molecular mechanisms that underlie susceptibility or tolerance to low O2. Previous studies have demonstrated that Notch signaling pathway regulates hypoxia tolerance in both Drosophila melanogaster and humans. However, the mechanisms mediating Notch-conferred hypoxia tolerance are largely unknown. In the current study, we delineate the evolutionarily conserved mechanisms underlying this hypoxia tolerant phenotype. We determined the role of a group of conserved genes that were obtained from a comparative genomic analysis of hypoxia-tolerant Drosophila melanogaster populations and human highlanders living at the high-altitude regions of the world (Tibetans, Ethiopians and Andeans). We developed a novel dual-UAS/Gal4 system that allows us to activate Notch signaling in the Eaat1-positive glial cells, which remarkably enhances hypoxia tolerance in Drosophila melanogaster, and, simultaneously, knock down a candidate gene in the same set of glial cells. Using this system, we discovered that the interactions between Notch signaling and bnl (fibroblast growth factor), croc (forkhead transcription factor C) or Mkk4 (mitogen-activated protein kinase kinase 4) are important for hypoxia tolerance, at least in part, through regulating neuronal development and survival under hypoxic conditions. Since these genetic mechanisms are evolutionarily conserved, this group of genes may serve as novel targets for developing therapeutic strategies and have a strong potential to be translated to humans to treat/prevent hypoxia-related diseases.

Time Domains of Hypoxia Responses and -Omics Insights

“…In hypoxia, Notch-responsive promoters are activated, and the HIF-1 transcription factor is recruited to these promoter sites ( Gustafsson et al, 2005 ). Notch pathway genes were shown to underlie hypoxia adaptation and increased Notch activity conferred improved hypoxia tolerance in Drosophila after hypoxia exposure for 200 generations ( Zhou et al, 2011 , 2021 ) and have been reported as putatively adaptive genes in Andean populations at high altitude ( Bigham et al, 2009 ). Research aimed at analyzing the cross-talk between HIF and NOTCH pathways in highland populations will provide greater insight into long-term hypoxia adaptations in humans ( O’Brien et al, 2022 ).…”

What can the common fruit fly teach us about stroke?: lessons learned from the hypoxic tolerant Drosophila melanogaster

“…Conversely, those with gain-of-function mutations are highly resistant to hypoxia (Zhou et al, 2011). Absence of Notch in excitatory amino acid transporter-positive glial cells decreases eclosion rates under hypoxic conditions, suggesting a possible mechanism for the tolerance (Zhou et al, 2021). Furthermore, Notch signaling elements interact with HIF pathways to regulate hypoxic adaptation, including high altitude adaptation in human populations (O'Brien et al, 2022).…”

Harnessing full-text publications for deep insights intoC. elegansandDrosophilaconnectomes

“…In contrast, the Drosophila Connectome illustrated a richer interaction network for the Notch pathway, indicating a more extensive exploration of its interacting partners in Drosophila or its suitability as a model organism for studying these interactions. Among the highlighted interactions were “NOTCH” interacts with “MKK4” (Zhou et al, 2021), “DMYC EXPRESSION” (Sun et al, 2008), “MORE THAN 300 GENES” (Ho, Pallavi & Artavanis-Tsakonas, 2015), and “AKAP200” (Bala Tannan et al, 2018), showcasing the pathway’s broad influence across Drosophila ’s genetic landscape.…”