Ascl1 Participates in Cajal-Retzius Cell Development in the Neocortex

Cajal-Retzius cells are essential pioneer neurons that guide neuronal migration in the developing neocortex. During development, Cajal-Retzius cells arise from distinct progenitor domains that line the margins of the dorsal telencephalon, or pallium. Here, we show that the proneural gene Ascl1 is expressed in Cajal-Retzius cell progenitors in the pallial septum, ventral pallium, and cortical hem. Using a short-term lineage trace, we demonstrate that it is primarily the Ascl1-expressing progenitors in the pallial septum and ventral pallium that differentiate into Cajal-Retzius cells. Accordingly, we found a small, albeit significant reduction in the number of Reelin(+) and Trp73(+) Cajal-Retzius cells in the Ascl1(-/-) neocortex. Conversely, using a gain-of-function approach, we found that Ascl1 induces the expression of both Reelin, a Cajal-Retzius marker, and Tbr1, a marker of pallial-derived neurons, in a subset of early-stage pallial progenitors, an activity that declines over developmental time. Taken together, our data indicate that the proneural gene Ascl1 is required and sufficient to promote the differentiation of a subset of Cajal-Retzius neurons during early neocortical development. Notably, this is the first study that reports a function for Ascl1 in the pallium, as this gene is best known for its role in specifying subpallial neuronal identities.