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An intrinsic mechanism of corticogenesis from embryonic stem cells

Nature volume 455, pages 351–357 (2008)Cite this article

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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.

References

  1. Wilson, S. W. & Houart, C. Early steps in the development of the forebrain. Dev. Cell 6, 167–181 (2004)

    Article  CAS  Google Scholar 

  2. Gunhaga, L., Jessell, T. M. & Edlund, T. Sonic hedgehog signaling at gastrula stages specifies ventral telencephalic cells in the chick embryo. Development 127, 3283–3293 (2000)

    CAS  PubMed  Google Scholar 

  3. Sur, M. & Rubenstein, J. L. Patterning and plasticity of the cerebral cortex. Science 310, 805–810 (2005)

    Article  ADS  CAS  Google Scholar 

  4. Schuurmans, C. & Guillemot, F. Molecular mechanisms underlying cell fate specification in the developing telencephalon. Curr. Opin. Neurobiol. 12, 26–34 (2002)

    Article  CAS  Google Scholar 

  5. Gotz, M. & Sommer, L. Cortical development: the art of generating cell diversity. Development 132, 3327–3332 (2005)

    Article  Google Scholar 

  6. Bayer, S. & Altman, J. Neocortical Development (Raven Press, 1991)

    Google Scholar 

  7. Molyneaux, B. J., Arlotta, P., Menezes, J. R. & Macklis, J. D. Neuronal subtype specification in the cerebral cortex. Nature Rev. Neurosci. 8, 427–437 (2007)

    Article  CAS  Google Scholar 

  8. Shen, Q. et al. The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells. Nature Neurosci. 9, 743–751 (2006)

    Article  CAS  Google Scholar 

  9. McConnell, S. K. & Kaznowski, C. E. Cell cycle dependence of laminar determination in developing neocortex. Science 254, 282–285 (1991)

    Article  ADS  CAS  Google Scholar 

  10. Frantz, G. D. & McConnell, S. K. Restriction of late cerebral cortical progenitors to an upper-layer fate. Neuron 17, 55–61 (1996)

    Article  CAS  Google Scholar 

  11. Vanderhaeghen, P. & Polleux, F. Developmental mechanisms patterning thalamocortical projections: intrinsic, extrinsic and in between. Trends Neurosci. 27, 384–391 (2004)

    Article  CAS  Google Scholar 

  12. Rash, B. G. & Grove, E. A. Area and layer patterning in the developing cerebral cortex. Curr. Opin. Neurobiol. 16, 25–34 (2006)

    Article  CAS  Google Scholar 

  13. O’Leary, D. D., Chou, S. J. & Sahara, S. Area patterning of the mammalian cortex. Neuron 56, 252–269 (2007)

    Article  Google Scholar 

  14. Ying, Q. L., Stavridis, M., Griffiths, D., Li, M. & Smith, A. Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nature Biotechnol. 21, 183–186 (2003)

    Article  CAS  Google Scholar 

  15. Smukler, S. R., Runciman, S. B. & Xu, S. &. van der Kooy. D. Embryonic stem cells assume a primitive neural stem cell fate in the absence of extrinsic influences. J. Cell Biol. 172, 79–90 (2006)

    Article  CAS  Google Scholar 

  16. Munoz-Sanjuan, I. & Brivanlou, A. H. Neural induction, the default model and embryonic stem cells. Nature Rev. Neurosci. 3, 271–280 (2002)

    Article  CAS  Google Scholar 

  17. Qian, X. et al. Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron 28, 69–80 (2000)

    Article  CAS  Google Scholar 

  18. Chen, J. K., Taipale, J., Cooper, M. K. & Beachy, P. A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 16, 2743–2748 (2002)

    Article  CAS  Google Scholar 

  19. Inoue, T., Nakamura, S. & Osumi, N. Fate mapping of the mouse prosencephalic neural plate. Dev. Biol. 219, 373–383 (2000)

    Article  CAS  Google Scholar 

  20. Hand, R. et al. Phosphorylation of Neurogenin2 specifies the migration properties and the dendritic morphology of pyramidal neurons in the neocortex. Neuron 48, 45–62 (2005)

    Article  CAS  Google Scholar 

  21. Polleux, F., Morrow, T. & Ghosh, A. Semaphorin 3A is a chemoattractant for cortical apical dendrites. Nature 404, 567–573 (2000)

    Article  ADS  CAS  Google Scholar 

  22. Hevner, R. F. et al. Beyond laminar fate: toward a molecular classification of cortical projection/pyramidal neurons. Dev. Neurosci. 25, 139–151 (2003)

    Article  CAS  Google Scholar 

  23. Britanova, O. et al. Satb2 is a postmitotic determinant for upper-layer neuron specification in the neocortex. Neuron 57, 378–392 (2008)

    Article  CAS  Google Scholar 

  24. Alcamo, E. A. et al. Satb2 regulates callosal projection neuron identity in the developing cerebral cortex. Neuron 57, 364–377 (2008)

    Article  CAS  Google Scholar 

  25. Dehay, C. & Kennedy, H. Cell-cycle control and cortical development. Nature Rev. Neurosci. 8, 438–450 (2007)

    Article  CAS  Google Scholar 

  26. Hevner, R. F. From radial glia to pyramidal-projection neuron: transcription factor cascades in cerebral cortex development. Mol. Neurobiol. 33, 33–50 (2006)

    Article  CAS  Google Scholar 

  27. Noctor, S. C., Martinez-Cerdeno, V., Ivic, L. & Kriegstein, A. R. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nature Neurosci. 7, 136–144 (2004)

    Article  CAS  Google Scholar 

  28. Gaillard, A., Gaillard, F. & Roger, M. Neocortical grafting to newborn and adult rats: developmental, anatomical and functional aspects. Adv. Anat. Embryol. Cell Biol. 148, 1–86 (1998)

    Article  CAS  Google Scholar 

  29. Wernig, M. et al. Tau EGFP embryonic stem cells: an efficient tool for neuronal lineage selection and transplantation. J. Neurosci. Res. 69, 918–924 (2002)

    Article  CAS  Google Scholar 

  30. Paxinos, G. The Rat Nervous System (Academic, 1995)

    Google Scholar 

  31. Pinaudeau, C., Gaillard, A. & Roger, M. Stage of specification of the spinal cord and tectal projections from cortical grafts. Eur. J. Neurosci. 12, 2486–2496 (2000)

    Article  CAS  Google Scholar 

  32. Ebrahimi-Gaillard, A., Guitet, J., Garnier, C. & Roger, M. Topographic distribution of efferent fibers originating from homotopic or heterotopic transplants: heterotopically transplanted neurons retain some of the developmental characteristics corresponding to their site of origin. Brain Res. Dev. Brain Res. 77, 271–283 (1994)

    Article  CAS  Google Scholar 

  33. Barbe, M. F. & Levitt, P. Age-dependent specification of the corticocortical connections of cerebral grafts. J. Neurosci. 15, 1819–1834 (1995)

    Article  CAS  Google Scholar 

  34. Armentano, M. et al. COUP-TFI regulates the balance of cortical patterning between frontal/motor and sensory areas. Nature Neurosci. 10, 1277–1286 (2007)

    Article  CAS  Google Scholar 

  35. Sansom, S. N. et al. Genomic characterisation of a Fgf-regulated gradient-based neocortical protomap. Development 132, 3947–3961 (2005)

    Article  CAS  Google Scholar 

  36. Lee, S. H., Lumelsky, N., Studer, L., Auerbach, J. M. & McKay, R. D. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nature Biotechnol. 18, 675–679 (2000)

    Article  CAS  Google Scholar 

  37. Wichterle, H., Lieberam, I., Porter, J. A. & Jessell, T. M. Directed differentiation of embryonic stem cells into motor neurons. Cell 110, 385–397 (2002)

    Article  CAS  Google Scholar 

  38. Andersson, E. et al. Identification of intrinsic determinants of midbrain dopamine neurons. Cell 124, 393–405 (2006)

    Article  CAS  Google Scholar 

  39. Bibel, M. et al. Differentiation of mouse embryonic stem cells into a defined neuronal lineage. Nature Neurosci. 7, 1003–1009 (2004)

    Article  CAS  Google Scholar 

  40. Glaser, T. & Brustle, O. Retinoic acid induction of ES-cell-derived neurons: the radial glia connection. Trends Neurosci. 28, 397–400 (2005)

    Article  CAS  Google Scholar 

  41. Watanabe, K. et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nature Neurosci. 8, 288–296 (2005)

    Article  CAS  Google Scholar 

  42. Gaillard, A. et al. Reestablishment of damaged adult motor pathways by grafted embryonic cortical neurons. Nature Neurosci. 10, 1294–1299 (2007)

    Article  CAS  Google Scholar 

  43. Puelles, L. Thoughts on the development, structure and evolution of the mammalian and avian telencephalic pallium. Phil. Trans. R. Soc. Lond. B 356, 1583–1598 (2001)

    Article  CAS  Google Scholar 

  44. Frost, S. B., Milliken, G. W., Plautz, E. J., Masterton, R. B. & Nudo, R. J. Somatosensory and motor representations in cerebral cortex of a primitive mammal (Monodelphis domestica): a window into the early evolution of sensorimotor cortex. J. Comp. Neurol. 421, 29–51 (2000)

    Article  CAS  Google Scholar 

  45. von Economo, C. & Koskinas, G. The Cytoarchitectonics of the Adult Human Cortex (Springer, 1925)

    Google Scholar 

Download references

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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Authors and 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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Supplementary information

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. (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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