| First Author | Zhang S | Year | 2021 |
| Journal | J Neurosci | Volume | 41 |
| Issue | 2 | Pages | 251-268 |
| PubMed ID | 33208471 | Mgi Jnum | J:299965 |
| Mgi Id | MGI:6501263 | Doi | 10.1523/JNEUROSCI.0731-20.2020 |
| Citation | Zhang S, et al. (2021) HIFalpha Regulates Developmental Myelination Independent of Autocrine Wnt Signaling. J Neurosci 41(2):251-268 |
| abstractText | The developing CNS is exposed to physiological hypoxia, under which hypoxia-inducible factor alpha (HIFalpha) is stabilized and plays a crucial role in regulating neural development. The cellular and molecular mechanisms of HIFalpha in developmental myelination remain incompletely understood. A previous concept proposes that HIFalpha regulates CNS developmental myelination by activating the autocrine Wnt/beta-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 HIFalpha-regulated developmental myelination. At the cellular level, we found that HIFalpha was required for developmental myelination by transiently controlling upstream OPC differentiation but not downstream oligodendrocyte maturation and that HIFalpha dysregulation in OPCs but not oligodendrocytes disturbed normal developmental myelination. We demonstrated that HIFalpha 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 HIFalpha-regulated OPC differentiation and myelination. We further identified HIFalpha-Sox9 regulatory axis as an underlying molecular mechanism in HIFalpha-regulated OPC differentiation. Our findings support a concept shift in our mechanistic understanding of HIFalpha-regulated CNS myelination from the previous Wnt-dependent view to a Wnt-independent one and unveil a previously unappreciated HIFalpha-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 alpha (HIFalpha) is a key regulator that adapts neural cells to physiological and pathologic hypoxic cues. The role and mechanism of HIFalpha 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 HIFalpha-regulated developmental myelination and suggest the potential of intervening with an oligodendroglial HIFalpha-mediated signaling pathway to mitigate disturbed myelination in premature white matter injury. |
