Retinoic acid is required for oligodendrocyte precursor cell production and differentiation in the postnatal mouse corpus callosum.

Myelination of the central nervous system (CNS) relies on the production and differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs). During the first month of postnatal life, OPCs that populate the corpus callosum (CC) arise from neural stem cells (NSCs) in the subcallosal subventricular zone (SVZ), and then differentiate to generate myelinating OLs. However, the signals that regulate these processes are not fully understood. In this study, we show that endogenous expression of the retinoic acid (RA)-synthesizing enzyme retinaldehyde dehydrogenase 2 (RALDH2) is required for OPC generation and differentiation in the postnatal subcortical white matter. In male and female pups, conditional deletion of Raldh2 reduced OPC numbers and differentiation. Moreover, decreased OPC numbers coincided with reductions in NSC survival and expression of the sonic hedgehog (SHH) signaling effector protein Gli1 in the SVZ. Additionally, GFAP expression in the CC was decreased, and cortical neuron numbers were altered. Our work suggests a role for endogenous RALDH2-dependent RA synthesis in OPC production and differentiation in the CC, as well as in the development of other cell types derived from NSCs in the embryonic ventricular zone (VZ)and SVZ, as well as the postnatal subcallosal SVZ. SIGNIFICANCE STATEMENT Postnatal forebrain myelination requires the production of oligodendrocytes (OLs), but the signals ensuring normal numbers of OLs have not been fully described. We demonstrate that loss of the retinoic acid (RA)-synthesizing enzyme retinaldehyde dehydrogenase 2 (RALDH2) decreased the number and differentiation of OL precursor cells (OPCs), leading to a deficit in OLs. These reductions co-occurred with increased death of neural stem cells (NSC), reduced expression a sonic hedgehog (SHH) pathway effector, and altered development of NSC-derived neurons and white matter astrocytes. Our results suggest that endogenous RA synthesis is required for the development of NSC-derived forebrain cells.