PT - JOURNAL ARTICLE AU - Nguyet Le AU - Timothy Hufford AU - Rachel Brewster TI - Hypoxia Regulation of <em>ndrgs</em> AID - 10.1101/2020.12.16.422782 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.12.16.422782 4099 - http://biorxiv.org/content/early/2020/12/18/2020.12.16.422782.short 4100 - http://biorxiv.org/content/early/2020/12/18/2020.12.16.422782.full AB - Many organisms rely on oxygen to generate energy in the form of adenosine triphosphate (ATP). During severe hypoxia, the production of ATP decreases due to diminished activity of the electron transport chain, leading to cell damage or death. Conversely, excessive oxygen causes oxidative stress that is equally damaging to cells. To mitigate pathological outcomes, organisms have evolved mechanisms to adapt to fluctuations in oxygen levels. Zebrafish embryos are remarkably hypoxia-tolerant, surviving anoxia (zero oxygen) for hours in a hypometabolic, energy-conserving state. To begin to unravel underlying mechanisms, we analyze here the distribution and hypoxia-dependent regulation of members of the N-myc Downstream Regulated Gene (Ndrg) family, Ndrg 1-4. These genes have primarily been studied in cancer cells, and hence little is understood about their normal function. We show here using in situ hybridization that, under normoxic conditions, ndrgs are expressed in metabolically-demanding organs of the zebrafish embryo, such as the brain, kidney, and heart. Following exposure of embryos to different severity and durations of hypoxia, we observed that ndrgs are differentially regulated and that ndrg1a is the most responsive member of this family, with nine-fold upregulation following prolonged anoxia. We further show that this treatment resulted in de novo expression of ndrg1a in tissues where it is not observed under normoxia, such as head vasculature, the inner ear, and somites. These findings provide an entry point into understanding the role of this conserved gene family in hypoxia adaptation of normal cells.Competing Interest StatementThe authors have declared no competing interest.NDRGN-myc downstream regulated geneHIF-1αHypoxia-inducible factor 1 alphaHREHypoxia response elementPHD2Prolyl hydroxylase domain protein 2VHLvon Hippel-Lindau proteinEPOErythropoietinVEGFVascular endothelial growth factorCREBcAMP-response element binding proteinMycMyelocytomatosis proto-oncogene, basic helix-loop-helix transcription factorNF-kBNuclear factor kappa-light-chain-enhancer of activated B cellsSTATSignal transducer and activator of transcriptionDrg1Downregulated gene 1Cap43Calcium associated protein 43 kDaRit42Reduced in tumor, 42 kDaRTPReducing agents and tunicamycin-responsive proteinPROXY-1Protein regulated by oxygen 1AP-1/2Activator proteins 1 &amp; 2LAMP1Lysosomal-associated membrane protein 1Rab4Ras-related protein Rab-4ATNF-αTumor necrosis factor alphaWISHWhole-mount in situ hybridizationIgfbp-1insulin-like growth factor-binding protein 1