Abstract

The developing CNS is exposed to physiological hypoxia, under which hypoxia inducible factor alpha (HIF) is stabilized and plays a crucial role in regulating neural development. The cellular and molecular mechanisms of HIF in developmental myelination remain incompletely understood. Previous concept proposes that HIF 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 evidences supporting an alternative understanding of oligodendroglial HIF-regulated developmental myelination. At the cellular level, we found that HIF was required for developmental myelination by transiently controlling upstream OPC differentiation but not downstream oligodendrocyte maturation and that HIF dysregulation in OPCs but not oligodendrocytes disturbed normal developmental myelination. We demonstrated that HIF 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 HIF-regulated OPC differentiation and myelination. We further identified HIF-Sox9 regulatory axis as an underlying molecular mechanism in HIF-regulated OPC differentiation. Our findings support a concept shift in our mechanistic understanding of HIF-regulated CNS myelination from the previous Wnt-dependent view to a Wnt-independent one and unveil a previously unappreciated HIF-Sox9 pathway in regulating OPC differentiation.