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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,4,30]]},"abstract":"<jats:p>\n                    The mammalian CNS is capable of tolerating chronic hypoxia, but cell type-specific responses to this stress have not been systematically characterized. In the Norrin KO (\n                    <jats:italic>Ndp<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>KO<\/jats:italic>\n                    <\/jats:sup>\n                    ) mouse, a model of familial exudative vitreoretinopathy (FEVR), developmental hypovascularization of the retina produces chronic hypoxia of inner nuclear-layer (INL) neurons and Muller glia. We used single-cell RNA sequencing, untargeted metabolomics, and metabolite labeling from\n                    <jats:sup>13<\/jats:sup>\n                    C-glucose to compare WT and\n                    <jats:italic>Ndp<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>KO<\/jats:italic>\n                    <\/jats:sup>\n                    retinas. In\n                    <jats:italic>Ndp<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>KO<\/jats:italic>\n                    <\/jats:sup>\n                    retinas, we observe gene expression responses consistent with hypoxia in Muller glia and retinal neurons, and we find a metabolic shift that combines reduced flux through the TCA cycle with increased synthesis of serine, glycine, and glutathione. We also used single-cell RNA sequencing to compare the responses of individual cell types in\n                    <jats:italic>Ndp<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>KO<\/jats:italic>\n                    <\/jats:sup>\n                    retinas with those in the hypoxic cerebral cortex of mice that were housed for 1 week in a reduced oxygen environment (7.5% oxygen). In the hypoxic cerebral cortex, glial transcriptome responses most closely resemble the response of Muller glia in the\n                    <jats:italic>Ndp<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>KO<\/jats:italic>\n                    <\/jats:sup>\n                    retina. In both retina and brain, vascular endothelial cells activate a previously dormant tip cell gene expression program, which likely underlies the adaptive neoangiogenic response to chronic hypoxia. These analyses of retina and brain transcriptomes at single-cell resolution reveal both shared and cell type-specific changes in gene expression in response to chronic hypoxia, implying both shared and distinct cell type-specific physiologic responses.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1821122116","type":"journal-article","created":{"date-parts":[[2019,4,16]],"date-time":"2019-04-16T15:49:52Z","timestamp":1555429792000},"page":"9103-9114","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":74,"title":["Hypoxia tolerance in the Norrin-deficient retina and the chronically hypoxic brain studied at single-cell resolution"],"prefix":"10.1073","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6291-6688","authenticated-orcid":false,"given":"Jacob S.","family":"Heng","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"},{"name":"Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9542-6212","authenticated-orcid":false,"given":"Amir","family":"Rattner","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve L.","family":"Stein-O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"},{"name":"McKusick\u2013Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Briana L.","family":"Winer","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"},{"name":"McKusick\u2013Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5527-6643","authenticated-orcid":false,"given":"Bryan W.","family":"Jones","sequence":"additional","affiliation":[{"name":"Moran Eye Center, University of Utah, Salt Lake City, UT 84132;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary J.","family":"Vernon","sequence":"additional","affiliation":[{"name":"McKusick\u2013Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loyal A.","family":"Goff","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"},{"name":"McKusick\u2013Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8106-5460","authenticated-orcid":false,"given":"Jeremy","family":"Nathans","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"},{"name":"Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"},{"name":"Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"},{"name":"Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,4,15]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"238","DOI":"10.3389\/fneur.2015.00238","article-title":"Recovery potential after acute stroke","volume":"6","author":"Seitz RJ","year":"2015","unstructured":"RJ Seitz, GA Donnan, Recovery potential after acute stroke. 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