An intrinsic mechanism of corticogenesis from embryonic stem cells

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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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Figure 1: Differentiation of ESCs into cortical progenitors.
Figure 2: Generation of functional cortical neurons from ESCs in DDM plus cyclopamine.
Figure 3: ESC-derived neurons in DDM plus cyclopamine display morphological features of pyramidal neurons.
Figure 4: The sequential generation of the different subtypes of ESC-derived cortical neurons is similar to the in vivo situation, and is encoded within single cell lineages.
Figure 5: ESC-derived neurons display a wide range of layer-specific but selective area-specific patterns of neuronal projections when grafted in vivo.

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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Correspondence to Pierre Vanderhaeghen.

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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. (PDF 4906 kb)

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Gaspard, N., Bouschet, T., Hourez, R. et al. An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature 455, 351–357 (2008). https://doi.org/10.1038/nature07287

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