A Role for Proneural Genes in the Maturation of Cortical Progenitor Cells

We showed previously that the proneural genes Neurogenin1 (Ngn1) and Ngn2 are required to specify the phenotypes of early- and not late-born neurons in the neocortex, acting in part through repression of Mash1, a third cortically expressed proneural gene. The precise timing of Ngn1/2 specification activity was unexpected given these genes are expressed throughout cortical development, prompting us to search for a later function. Here we reveal that Ngn2 and Mash1 are expressed in a dynamic fashion, acquiring a cell cycle-biased, nonoverlapping distribution, with preferential expression in prospective basal progenitors, during mid corticogenesis. We also identified a new function for Ngn2 during this latter period, demonstrating that it is required to regulate the transit of cortical progenitors from the ventricular zone (VZ) to the subventricular zone. Notably, Ngn2 regulates progenitor maturation at least in part through repression of Mash1 as misexpression of Mash1 strongly enhanced progenitor cell exit from the VZ. Significantly, the ability of Mash1 to promote progenitor cell maturation occurred independently of its ability to respecify cortical cells and is thus a novel function for Mash1. Taken together, these data support a model whereby Ngn2 and Mash1 function together to regulate the zonal distribution of progenitors in the developing neocortex.