ASCL1 and OLIG2 Expression Dynamics Control Glial Cell Fate and Regional Diversity in the Dorsal Forebrain

Abstract

Gliogenesis is a multistep process in which glial progenitors are specified into migrating and proliferating precursor cells that subsequently differentiate into mature astrocytes and oligodendrocytes. How these developmental processes are coordinated to generate the diverse glial lineages across gray matter (GM) and white matter (WM) regions remains poorly understood. Here, we show that the basic-helix-loop-helix transcription factor ASCL1 serves as a direct mechanistic link between these processes in the dorsal forebrain. Notably, ASCL1 is dynamically expressed in glial progenitor cells, initiating in the ventricular zone, peaking in the intermediate zone, but is downregulated once glial cells enter the cortical plate. Lineage tracing of ASCL1+ progenitors demonstrates that they subsequently coexpress OLIG2 to generate both astrocytes and oligodendrocytes in an “outside-in” pattern starting from the upper cortex inward to the corpus callosum, the opposite pattern of neurogenesis. ASCL1 gain-of-function combined with OLIG2 loss-of-function reveals that sustained levels of ASCL1 are essential to induce sufficient levels of OLIG2 required to specify oligodendrocyte precursor cell (OPC) fate. Interestingly, a persistent ASCL1 expression also maintains OPCs in an undifferentiated, preneoplastic state into postnatal stages, in part by suppressing their differentiation into postmitotic oligodendrocytes. Together, these findings establish ASCL1 as a key regulator of the spatiotemporal order of glial lineage diversity in cortical GM and callosal WM and highlight ASCL1 dysregulation as an underlying developmental mechanism in the pathogenesis of gliomas.