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SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development

Nature Neuroscience volume 12, pages 1238–1247 (2009)Cite this article

Abstract

The neuronal diversity of the CNS emerges largely from controlled spatial and temporal segregation of cell type-specific molecular regulators. We found that the transcription factor SOX6 controls the molecular segregation of dorsal (pallial) from ventral (subpallial) telencephalic progenitors and the differentiation of cortical interneurons, regulating forebrain progenitor and interneuron heterogeneity. During corticogenesis in mice, SOX6 and SOX5 were largely mutually exclusively expressed in pallial and subpallial progenitors, respectively, and remained mutually exclusive in a reverse pattern in postmitotic neuronal progeny. Loss of SOX6 from pallial progenitors caused their inappropriate expression of normally subpallium-restricted developmental controls, conferring mixed dorsal-ventral identity. In postmitotic cortical interneurons, loss of SOX6 disrupted the differentiation and diversity of cortical interneuron subtypes, analogous to SOX5 control over cortical projection neuron development. These data indicate that SOX6 is a central regulator of both progenitor and cortical interneuron diversity during neocortical development.

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Figure 1: SOX6 and SOX5 are expressed in complementary populations of telencephalic progenitors and neuronal progeny during corticogenesis.
Figure 2: SOX6 and SOX5 are cross-repressive in pallial and subpallial telencephalic progenitor domains.
Figure 3: Loss of SOX6 function results in ectopic proneural gene expression in pallial progenitors and subpallial mantle zones.
Figure 4: Loss of SOX6 function results in abnormal early cortical interneuron differentiation, without a change in interneuron number.
Figure 5: Loss of SOX6 function disrupts the normal laminar position and morphology of cortical interneurons.
Figure 6: SOX6 is necessary for cortical interneuron subtype development.
Figure 7: Loss of SOX6 function produces an increased number of early- and late-born NPY-positive cortical interneurons.
Figure 8: SOX6 control over MGE-derived cortical interneuron subtype differentiation is population autonomous.

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Acknowledgements

We thank K. Billmers, A. Palmer, L. Pasquina, K. Quinn, D. Schuback, E. Sievert, A. Wheeler and T. Yamamoto for superb technical assistance, G. Fishell, R. Batista-Brito, G. Miyoshi, P. Arlotta, B. Molyneaux, H. Padmanabhan, F. Guillemot, Q. Ma, C. Cepko and L. Goodrich for helpful discussions and input, U. Berger for technical assistance with in situ hybridization, C. Lois, R. Hevner, V. Lefebvre, F. Guillemot, V. Pachnis and Y. Yanagawa for generously sharing mice, antibodies and reagents, and current and past members of our laboratory for helpful suggestions. This work was partially supported by grants from the US National Institutes of Health (NS49553 and NS45523; additional infrastructure supported by NS41590), the Travis Roy Foundation, the Spastic Paraplegia Foundation, the Massachusetts Spinal Cord Injury research program, and the Harvard Stem Cell Institute to J.D.M., and by the Jane and Lee Seidman Fund for CNS Research, and the Emily and Robert Pearlstein Fund for Nervous System Repair. E.A. was partially supported by a US National Institutes of Health individual predoctoral National Research Service Award fellowship (F31 NS060421). D.J. was partially supported by fellowships from the Swiss National Science Foundation and the Holcim Foundation. R.M.F. was partially supported by a National Science Foundation Graduate Research Fellowship.

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Author notes

  1. Denis Jabaudon

    Present address: Present address: Department of Basic Neurosciences and Clinic of Neurology, University of Geneva, Switzerland.,

Authors and Affiliations

  1. Departments of Neurosurgery and Neurology, Massachusetts General Hospital–Harvard Medical School Center for Nervous System Repair, Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA

    Eiman Azim, Denis Jabaudon, Ryann M Fame & Jeffrey D Macklis

  2. Nayef Al-Rodhan Laboratories, Massachusetts General Hospital, Boston, Massachusetts, USA

    Eiman Azim, Denis Jabaudon, Ryann M Fame & Jeffrey D Macklis

  3. Department of Stem Cell and Regenerative Biology, and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA

    Eiman Azim, Denis Jabaudon, Ryann M Fame & Jeffrey D Macklis

  4. Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA

    Ryann M Fame

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Contributions

E.A. and J.D.M. designed the overall experimental directions and specific analyses, and wrote and edited the manuscript. E.A. also performed all of the experiments and data analysis. D.J. co-performed the microarray experiments and assisted with interneuron quantification, microarray data evaluation, experimental design and data analysis, and manuscript writing and editing. R.M.F. performed whole-mount in situ hybridization/immunocytochemistry and assisted with BrdU/PH3 pallial progenitor analysis, microarray data evaluation, interneuron quantification, and manuscript editing. J.D.M. also contributed to data analysis and biological interpretation.

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Correspondence to Jeffrey D Macklis.

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Azim, E., Jabaudon, D., Fame, R. et al. SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development. Nat Neurosci 12, 1238–1247 (2009). https://doi.org/10.1038/nn.2387

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