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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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Change history

  • 18 September 2008

    In the AOP version of this paper, the x-axis of Figure 1c was incorrectly labelled. This was corrected for print on 18 September 2008.

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Acknowledgements

We thank G. Vassart, M. Pandolfo and members of the laboratory and IRIBHM for support and discussions. We are indebted to A. Bilheu for technical assistance, J.-M. Vanderwinden for help with confocal microscopy, and V. De Maertelaer for statistical analyses. We thank F. Polleux, B. Hassan and C. Blanpain for comments on the manuscript. We are grateful to S. Arber, A. Goffinet, R. Hevner, R. di Lauro, Y. Sasai, S. Stifani, M. Studer and V. Tarabykin for providing us with antibodies, and to Y.-A. Barde for providing Tau–GFP ESC lines. This work was funded by the Belgian FNRS, the Action de Recherches Concertées (ARC) Programs (to P.V. and S.N.S.), the Interuniversity Attraction Poles Program (IUAP), Belgian State, Federal Office, the Walloon Region Excellence Program CIBLES, the Belgian Queen Elizabeth Medical Foundation and a UCB Neuroscience Award (to P.V.), the Tournesol FNRS/CNRS Program (to P.V. and A.G.), Télévie (to S.N.S.), and a Marie Curie Grant (to T.B.). P.V. is a Senior Research Associate of the FNRS, and N.G., R.H., T.B., J.D. and L.P. were funded as Research Fellows of the FNRS.

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Affiliations

  1. IRIBHM (Institute for Interdisciplinary Research), Université Libre de Bruxelles (ULB)

    • Nicolas Gaspard
    • , Tristan Bouschet
    • , Jordane Dimidschstein
    • , Gilles Naeije
    • , Jelle van den Ameele
    • , Ira Espuny-Camacho
    • , Adèle Herpoel
    • , Lara Passante
    •  & Pierre Vanderhaeghen
  2. Laboratory of Neurophysiology, Université Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium

    • Raphael Hourez
    •  & Serge N. Schiffmann
  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

    • Afsaneh Gaillard

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Correspondence to Pierre Vanderhaeghen.

Supplementary information

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  1. 1.

    Supplementary Information

    The file contains Supplementary Notes, Supplementary Methods, Supplementary Figures 1-12 with Legends and Supplementary Tables 1-6 displaying additional data concerning the identity of the ES-derived progenitors and neurons in vitro and in vivo.

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https://doi.org/10.1038/nature07287

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