Oligodendrocyte-encoded HIF Function Couples Postnatal Myelination and White Matter Angiogenesis

Cell. 2014 Jul 17;158(2):383-396. doi: 10.1016/j.cell.2014.04.052. Epub 2014 Jul 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation
  • Corpus Callosum / metabolism
  • Endothelial Cells / cytology
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • In Vitro Techniques
  • Mice
  • Myelin Sheath / metabolism*
  • Neovascularization, Physiologic
  • Neural Stem Cells
  • Oligodendroglia / metabolism*
  • Oxygen / metabolism
  • Paracrine Communication
  • Proto-Oncogene Proteins / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism
  • Wnt Proteins / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Proto-Oncogene Proteins
  • Wnt Proteins
  • Wnt7a protein, mouse
  • Wnt7b protein, mouse
  • endothelial PAS domain-containing protein 1
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, mouse
  • Oxygen