Meningeal-derived retinoic acid regulates neurogenesis via suppression of Notch and Sox2

The meninges act as a regulator of brain development by secreting ligands that act on neural cells to regulate neurogenesis and neuronal migration. Meningeal-derived retinoic acid (RA) promotes neocortical neural progenitor cell cycle exit; however, the underlying molecular mechanism is unknown. Here, we used spatial transcriptomics and profiling of retinoic acid receptor α (RARα) DNA binding in Foxc1-mutant embryos that lack meninges-derived signals to identify potential neurogenic transcriptional mechanisms of RA signaling in telencephalic neural progenitors. This identified upregulation of Sox2 and Notch pathway genes, and RARα binds to the Sox2ot promoter, a long noncoding RNA that regulates Sox2 expression. Our experiments using maternal RA treatment and in utero electroporation in Foxc1 mutants support that meningeal-derived RA promotes neurogenesis by suppressing Notch signaling, a progenitor self-renewal pathway. Our findings elucidate a previously unknown mechanism of how meningeal RA coordinates neocortical development and provide insight into how defects in meningeal development may cause neurodevelopmental disorders.