title: Oligodendrocyte-encoded HIF function couples postnatal myelination and white matter angiogenesis.
abstract: Myelin sheaths provide critical functional and trophic support for axons in white matter tracts of the brain. Oligodendrocyte precursor cells (OPCs) have extraordinary metabolic requirements during development as they differentiate to produce multiple myelin segments, implying that they must first secure adequate access to blood supply. However, mechanisms that coordinate myelination and angiogenesis are unclear. Here, we show that oxygen tension, mediated by OPC-encoded hypoxia-inducible factor (HIF) function, is an essential regulator of postnatal myelination. Constitutive HIF1/2α stabilization resulted in OPC maturation arrest through autocrine activation of canonical Wnt7a/7b. Surprisingly, such OPCs also show paracrine activity that induces excessive postnatal white matter angiogenesis in vivo and directly stimulates endothelial cell proliferation in vitro. Conversely, OPC-specific HIF1/2α loss of function leads to insufficient angiogenesis in corpus callosum and catastrophic axon loss. These findings indicate that OPC-intrinsic HIF signaling couples postnatal white matter angiogenesis, axon integrity, and the onset of myelination in mammalian forebrain.
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Yuen
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Silbereis
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Amelie
authors.initials: A
authors.lastname: Griveau
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Chang
authors.affiliation: Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Daneman
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Stephen P J
authors.initials: SPJ
authors.lastname: Fancy
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA; Medical Science Training Program, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Hengameh
authors.initials: H
authors.lastname: Zahed
authors.affiliation: Division of Neonatology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Emin
authors.initials: E
authors.lastname: Maltepe
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA; Division of Neonatology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: rowitchd@peds.ucsf.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D003337:Corpus Callosum / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D009186:Myelin Sheath / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D058953:Neural Stem Cells; D009836:Oligodendroglia / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D019899:Paracrine Communication; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D011518:Proto-Oncogene Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051153:Wnt Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C490508:Wnt7a protein, mouse; C095937:Wnt7b protein, mouse; C494469:VHL protein, mouse