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Genetic interactions regulate hypoxia tolerance conferred by activating Notch in excitatory amino acid transporter 1-positive glial cells inDrosophila melanogaster
- Source :
- G3 (Bethesda, Md.), vol 11, iss 2, G3: Genes|Genomes|Genetics
- Publication Year :
- 2021
- Publisher :
- Oxford University Press (OUP), 2021.
-
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 this 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 D.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 D.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. Becausethese 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.
- Subjects :
- AcademicSubjects/SCI01140
genetic interactions
Candidate gene
Notch
AcademicSubjects/SCI00010
1.1 Normal biological development and functioning
Notch signaling pathway
Biology
AcademicSubjects/SCI01180
Fibroblast growth factor
03 medical and health sciences
0302 clinical medicine
Underpinning research
Receptors
Genetics
medicine
Animals
Drosophila Proteins
2.1 Biological and endogenous factors
Aetiology
Hypoxia
Molecular Biology
Transcription factor
Gene
Notch signaling
Genetics (clinical)
030304 developmental biology
Investigation
0303 health sciences
Receptors, Notch
Human Genome
Hypoxia (medical)
biology.organism_classification
Phenotype
Cell biology
Excitatory Amino Acid Transporter 1
eaat1-posive glia
Stroke
Drosophila melanogaster
AcademicSubjects/SCI00960
medicine.symptom
Neuroglia
030217 neurology & neurosurgery
Biotechnology
Subjects
Details
- ISSN :
- 21601836
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- G3 Genes|Genomes|Genetics
- Accession number :
- edsair.doi.dedup.....79f7c6a2232a56fab8f502b1c51298b1