Dual inhibition of MAPK/ERK and BMP signaling induces entorhinal-like identity in mouse ESC-derived pallial progenitors

The mechanisms that determine distinct pallial identities during embryonic corticogenesis are not fully understood. In vitro modeling of neurogenesis facilitates the dissection of the effects of different signaling pathways on neural progenitor specification. The central role of Wnt signaling in directing dorsal telencephalic progenitors to the isocortex or hippocampus has been elucidated. The present study shows that the timely inhibition of MAPK/ERK and BMP signaling in neuralized mouse embryonic stem cells specifies a cell identity characteristic of the allocortex. Comparison of the global gene expression profiles of neural cells obtained by MAPK/ERK and BMP inhibition (MiBi cells) with those of cells from early postnatal encephalic regions emphasizes a pallial identity of MiBi cells, distinct from isocortical and hippocampal cells. MiBi cells display a unique pattern of gene expression and connectivity, and exhibit molecular and electrophysiological features consistent with the entorhinal cortex. Our findings indicate that early changes in cell signaling can specify distinct pallial fates that are maintained by specific neuronal lineages regardless of subsequent embryonic morphogenetic interactions and can determine their functional connectivity.