title: Hypoxia inducible factor-1α (HIF-1α) is required for neural stem cell maintenance and vascular stability in the adult mouse SVZ.
abstract: HIF-1α is a hypoxia-inducible protein that regulates many cell and molecular processes, including those involved in angiogenesis and stem cell maintenance. Prior studies demonstrated constitutive HIF-1α stabilization in neural stem cells (NSCs) of the adult mouse SVZ, but its role there has not been elucidated. Here, we tested the hypothesis that HIF-1α plays an essential role in the maintenance of adult NSCs and stabilization of the SVZ vascular niche using conditional, tamoxifen-inducible Hif1a knock-out mice. We generated nestin-CreER(T2)/R26R-YFP/Hif1a(fl/fl) triple transgenic mice, to enable tamoxifen-inducible Hif1a gene inactivation in nestin-expressing NSCs within the adult SVZ. Hif1a gene deletion resulted in a significant loss of YFP(+) NSCs within the SVZ by 45 d post recombination, which was preceded by significant regression of the SVZ vasculature at 14 d, and concomitant decrease of VEGF expression by NSCs. Loss of YFP(+) NSCs following Hif1a gene inactivation in vivo was likely an indirect consequence of vascular regression, since YFP(+) neurosphere formation over serial passage was unaffected. These results identify NSC-encoded HIF-1α as an essential factor in the maintenance of the adult SVZ, and demonstrate that NSCs within the SVZ maintain the integrity of their vascular niche through HIF-1α-mediated signaling mechanisms.
authors.affiliation: Department of Neurosciences, University of New Mexico Health Sciences Center, School of Medicine, Albuquerque, New Mexico 87131.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neurosciences, University of New Mexico Health Sciences Center, School of Medicine, Albuquerque, New Mexico 87131.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Candelario
authors.affiliation: Department of Neurosciences, University of New Mexico Health Sciences Center, School of Medicine, Albuquerque, New Mexico 87131.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Thomas
authors.affiliation: Department of Neurosciences, University of New Mexico Health Sciences Center, School of Medicine, Albuquerque, New Mexico 87131.
authors.forename: Ruth
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Neurosciences, University of New Mexico Health Sciences Center, School of Medicine, Albuquerque, New Mexico 87131.
authors.forename: Kandis
authors.identifier: http://orcid.org/0000-0002-3877-5448
authors.initials: K
authors.lastname: Wright
authors.affiliation: Department of Neurosciences, University of New Mexico Health Sciences Center, School of Medicine, Albuquerque, New Mexico 87131.
authors.forename: Amber
authors.initials: A
authors.lastname: Messier
authors.affiliation: Department of Neurosciences, University of New Mexico Health Sciences Center, School of Medicine, Albuquerque, New Mexico 87131 leeanna@salud.unm.edu.
authors.forename: Lee Anna
authors.identifier: http://orcid.org/0000-0003-0294-5262
authors.initials: LA
authors.lastname: Cunningham
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology*; D000818:Animals; D002560:Cerebrovascular Circulation / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency* / Q000235:genetics; D020547:Lateral Ventricles / Q000098:blood supply* / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000502:physiology*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: hypoxia; stem cell niche; vasculature