Journal
CELL
Volume 158, Issue 2, Pages 383-396Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.04.052
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Funding
- National Multiple Sclerosis Society (NMSS)
- NIGMS [T32 GM007449-36]
- Ruth Kirschstein NRSA fellowship from NINDS [F31 NS076254-03]
- NICHD [HD072544]
- NINDS [NS040511, P01NS083513]
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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 HIF1/2 alpha stabilization resulted in OPC maturation arrest through autocrine activation of canonical Wnt7 alpha/7 beta. 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 HIF1/2 alpha 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.
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