HIFα regulates developmental myelination independent of autocrine Wnt signaling

Abstract

words)The developing CNS is exposed to physiological hypoxia, under which hypoxia inducible factor alpha (HIFα) is stabilized and plays a crucial role in regulating neural development. The cellular and molecular mechanism of HIFα in developmental myelination remain incompletely understood. 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 the 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. Significant statement (100 words)Promoting disturbed developmental myelination is a promising option in treating periventricular leukomalacia, a major form of brain white matter injury affecting premature infants. In the developing CNS, HIFα is a master regulator that adapts neural cells to physiological and pathological hypoxic cues. The role and mechanism of HIFα in oligodendroglial myelination, which is developmentally disturbed in preterm infants affected with 3 periventricular leukomalacia, are 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 oligodendroglial HIFα-mediated signaling pathway in mitigating disturbed myelination in premature white matter injury.