Ascl1 promotes OPC specification across species and central nervous system regions and its gliogenic function is regulated by phosphorylation.

In the developing central nervous system (CNS), neural progenitors first generate neurons before making astrocytes and oligodendrocytes. This transition from neurogenesis to gliogenesis represents a fundamental developmental switch in the vertebrate CNS, but the molecular mechanisms that drive progenitors toward glial fates are not fully understood. In this study, we identify Ascl1 as a conserved regulator of oligodendrocyte lineage specification and demonstrate that this function is regulated by phosphorylation downstream of FGF signaling. We used single-cell sequencing approaches in zebrafish spinal cord and mouse neocortex to show that Ascl1 is expressed in multipotent neural progenitor cells as they transition toward the oligodendrocyte lineage. Moreover, we performed loss of function experiments in zebrafish and mouse and found that Ascl1 promotes oligodendrocyte fate specification across species and CNS regions. We further demonstrated that phosphorylation of ASCL1 is required to direct progenitors toward OPC fate in the mouse neocortex, likely downstream of FGF signaling. Together, our data reveal an FGF-ASCL1 signaling axis that couples extrinsic signaling inputs to intrinsic transcriptional programs governing oligodendrogenesis.