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

Abstract

The mechanisms that determine distinct embryonic pallial identities remain elusive. The central role of Wnt signaling in directing dorsal telencephalic progenitors to the isocortex or hippocampus has been elucidated. Here, we show that timely inhibition of MAPK/ERK and BMP signaling in neuralized mouse embryonic stem cells (ESCs) specifies a cell identity characteristic of the allocortex. Comparison of the global gene expression profiles of neural cells generated by MAPK/ERK and BMP inhibition (MiBi cells) with those of cells from early postnatal encephalic regions reveals a pallial identity of MiBi cells, distinct from isocortical and hippocampal cells. MiBi cells display a unique pattern of gene expression and connectivity, and share molecular and electrophysiological features with the entorhinal cortex. Our results suggest that early changes in cell signaling can specify distinct pallial fates that are maintained by specific neuronal lineages independent of subsequent embryonic morphogenetic interactions and can determine their functional connectivity.

Keywords: BMP; HD-MEAs; MAPK/ERK; assembloids; axonogenesis; connectivity; enthorinal cortex; neural network; pallium patterning; theta activity.