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Research Articles, Development/Plasticity/Repair

HIFα Regulates Developmental Myelination Independent of Autocrine Wnt Signaling

Sheng Zhang, Yan Wang, Jie Xu, Bokyung Kim, Wenbin Deng and Fuzheng Guo
Journal of Neuroscience 13 January 2021, 41 (2) 251-268; DOI: https://doi.org/10.1523/JNEUROSCI.0731-20.2020
Sheng Zhang
1Department of Neurology, School of Medicine, University of California, Davis, California 95616
3Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children—Northern California, Sacramento, California 95817
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Yan Wang
1Department of Neurology, School of Medicine, University of California, Davis, California 95616
3Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children—Northern California, Sacramento, California 95817
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Jie Xu
3Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children—Northern California, Sacramento, California 95817
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Bokyung Kim
1Department of Neurology, School of Medicine, University of California, Davis, California 95616
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Wenbin Deng
2Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California 95616
3Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children—Northern California, Sacramento, California 95817
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Fuzheng Guo
1Department of Neurology, School of Medicine, University of California, Davis, California 95616
3Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children—Northern California, Sacramento, California 95817
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Abstract

The developing CNS is exposed to physiological hypoxia, under which hypoxia-inducible factor α (HIFα) is stabilized and plays a crucial role in regulating neural development. The cellular and molecular mechanisms of HIFα in developmental myelination remain incompletely understood. A previous concept proposes that HIFα regulates CNS developmental myelination by activating the autocrine Wnt/β-catenin signaling in oligodendrocyte progenitor cells (OPCs). Here, by analyzing a battery of genetic mice of both sexes, we presented in vivo evidence supporting an alternative understanding of oligodendroglial HIFα-regulated developmental myelination. At the cellular level, we found that HIFα was required for developmental myelination by transiently controlling upstream OPC differentiation but not downstream oligodendrocyte maturation and that HIFα dysregulation in OPCs but not oligodendrocytes disturbed normal developmental myelination. We demonstrated that HIFα played a minor, if any, role in regulating canonical Wnt signaling in the oligodendroglial lineage or in the CNS. At the molecular level, blocking autocrine Wnt signaling did not affect HIFα-regulated OPC differentiation and myelination. We further identified HIFα–Sox9 regulatory axis as an underlying molecular mechanism in HIFα-regulated OPC differentiation. Our findings support a concept shift in our mechanistic understanding of HIFα-regulated CNS myelination from the previous Wnt-dependent view to a Wnt-independent one and unveil a previously unappreciated HIFα–Sox9 pathway in regulating OPC differentiation.

SIGNIFICANCE STATEMENT Promoting disturbed developmental myelination is a promising option in treating diffuse white matter injury, previously called periventricular leukomalacia, a major form of brain injury affecting premature infants. In the developing CNS, hypoxia-inducible factor α (HIFα) is a key regulator that adapts neural cells to physiological and pathologic hypoxic cues. The role and mechanism of HIFα in oligodendroglial myelination, which is severely disturbed in preterm infants affected with diffuse white matter injury, is incompletely understood. Our findings presented here represent a concept shift in our mechanistic understanding of HIFα-regulated developmental myelination and suggest the potential of intervening with an oligodendroglial HIFα-mediated signaling pathway to mitigate disturbed myelination in premature white matter injury.

  • hypoxia inducible factor
  • myelination
  • oligodendrocyte progenitor cells
  • oligodendrocytes
  • oligodendroglial differentiation
  • oligodendroglial maturation

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The Journal of Neuroscience: 41 (2)
Journal of Neuroscience
Vol. 41, Issue 2
13 Jan 2021
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HIFα Regulates Developmental Myelination Independent of Autocrine Wnt Signaling
Sheng Zhang, Yan Wang, Jie Xu, Bokyung Kim, Wenbin Deng, Fuzheng Guo
Journal of Neuroscience 13 January 2021, 41 (2) 251-268; DOI: 10.1523/JNEUROSCI.0731-20.2020

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HIFα Regulates Developmental Myelination Independent of Autocrine Wnt Signaling
Sheng Zhang, Yan Wang, Jie Xu, Bokyung Kim, Wenbin Deng, Fuzheng Guo
Journal of Neuroscience 13 January 2021, 41 (2) 251-268; DOI: 10.1523/JNEUROSCI.0731-20.2020
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Keywords

  • hypoxia inducible factor
  • myelination
  • oligodendrocyte progenitor cells
  • oligodendrocytes
  • oligodendroglial differentiation
  • oligodendroglial maturation

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