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

被引:314
作者
Yuen, Tracy J. [1 ,2 ]
Silbereis, John C. [1 ,2 ,3 ]
Griveau, Amelie [1 ,2 ]
Chang, Sandra M. [1 ,2 ]
Daneman, Richard [4 ]
Fancy, Stephen P. J. [1 ,2 ]
Zahed, Hengameh [1 ,2 ,5 ]
Maltepe, Emin [6 ]
Rowitch, David H. [1 ,2 ,6 ]
机构
[1] Univ Calif San Francisco, Eli & Edythe Broad Inst Stem Cell Res & Regenerat, Dept Pediat, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Grad Program Neurosci, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA
[5] Univ Calif San Francisco, Med Sci Training Program, San Francisco, CA 94143 USA
[6] Univ Calif San Francisco, Div Neonatol, San Francisco, CA 94143 USA
关键词
CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; NUCLEAR TRANSLOCATOR ARNT; HYPOXIA-INDUCIBLE FACTORS; BETA-CATENIN; MULTIPLE-SCLEROSIS; ENDOTHELIAL-CELLS; AXONAL INTEGRITY; PROGENITOR CELLS; CEREBRAL-PALSY;
D O I
10.1016/j.cell.2014.04.052
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:383 / 396
页数:14
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