1. IRIBHM (Institute for Interdisciplinary Research), Université Libre de Bruxelles (ULB)
2. Laboratory of Neurophysiology, Université Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium
3. Institut de Physiologie et Biologie Cellulaires, Université de Poitiers, Centre National de la Recherche Scientifique (CNRS), 40 avenue du recteur Pineau, Poitiers, F-86022, France

Correspondence to: Pierre Vanderhaeghen¹ Correspondence and requests for materials should be addressed to P.V. (Email: pierre.vanderhaeghen@ulb.ac.be).

Abstract

The cerebral cortex develops through the coordinated generation of dozens of neuronal subtypes, but the mechanisms involved remain unclear. Here we show that mouse embryonic stem cells, cultured without any morphogen but in the presence of a sonic hedgehog inhibitor, recapitulate in vitro the major milestones of cortical development, leading to the sequential generation of a diverse repertoire of neurons that display most salient features of genuine cortical pyramidal neurons. When grafted into the cerebral cortex, these neurons develop patterns of axonal projections corresponding to a wide range of cortical layers, but also to highly specific cortical areas, in particular visual and limbic areas, thereby demonstrating that the identity of a cortical area can be specified without any influence from the brain. The discovery of intrinsic corticogenesis sheds new light on the mechanisms of neuronal specification, and opens new avenues for the modelling and treatment of brain diseases.

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