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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References
Schuurmans, C. & Guillemot, F. Molecular mechanisms underlying cell fate specification in the developing telencephalon. Curr. Opin. Neurobiol. 12, 26–34 (2002).
Wonders, C.P. & Anderson, S.A. The origin and specification of cortical interneurons. Nat. Rev. Neurosci. 7, 687–696 (2006).
Molyneaux, B.J., Arlotta, P., Menezes, J.R. & Macklis, J.D. Neuronal subtype specification in the cerebral cortex. Nat. Rev. Neurosci. 8, 427–437 (2007).
Fode, C. et al. A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons. Genes Dev. 14, 67–80 (2000).
Parras, C.M. et al. Divergent functions of the proneural genes Mash1 and Ngn2 in the specification of neuronal subtype identity. Genes Dev. 16, 324–338 (2002).
Butt, S.J. et al. The temporal and spatial origins of cortical interneurons predict their physiological subtype. Neuron 48, 591–604 (2005).
Miyoshi, G., Butt, S.J., Takebayashi, H. & Fishell, G. Physiologically distinct temporal cohorts of cortical interneurons arise from telencephalic Olig2-expressing precursors. J. Neurosci. 27, 7786–7798 (2007).
Flames, N. et al. Delineation of multiple subpallial progenitor domains by the combinatorial expression of transcriptional codes. J. Neurosci. 27, 9682–9695 (2007).
Wonders, C.P. et al. A spatial bias for the origins of interneuron subgroups within the medial ganglionic eminence. Dev. Biol. 314, 127–136 (2008).
Fogarty, M. et al. Spatial genetic patterning of the embryonic neuroepithelium generates GABAergic interneuron diversity in the adult cortex. J. Neurosci. 27, 10935–10946 (2007).
Ascoli, G.A. et al. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat. Rev. Neurosci. 9, 557–568 (2008).
Flames, N. & Marin, O. Developmental mechanisms underlying the generation of cortical interneuron diversity. Neuron 46, 377–381 (2005).
Corbin, J.G., Nery, S. & Fishell, G. Telencephalic cells take a tangent: non-radial migration in the mammalian forebrain. Nat. Neurosci. 4 Suppl, 1177–1182 (2001).
Levitt, P., Eagleson, K.L. & Powell, E.M. Regulation of neocortical interneuron development and the implications for neurodevelopmental disorders. Trends Neurosci. 27, 400–406 (2004).
Armijo, J.A., Valdizan, E.M., De Las Cuevas, I. & Cuadrado, A. Rev. Neurol. Advances in the physiopathology of epileptogenesis: molecular aspects. 34, 409–429 (2002).
Rubenstein, J.L. & Merzenich, M.M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003).
Lewis, D.A. GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia. Brain Res. Brain Res. Rev. 31, 270–276 (2000).
Arlotta, P. et al. Neuronal subtype–specific genes that control corticospinal motor neuron development in vivo. Neuron 45, 207–221 (2005).
Chen, B., Schaevitz, L.R. & McConnell, S.K. Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex. Proc. Natl. Acad. Sci. USA 102, 17184–17189 (2005).
Chen, J.G., Rasin, M.R., Kwan, K.Y. & Sestan, N. Zfp312 is required for subcortical axonal projections and dendritic morphology of deep-layer pyramidal neurons of the cerebral cortex. Proc. Natl. Acad. Sci. USA 102, 17792–17797 (2005).
Lai, T. et al. SOX5 controls the sequential generation of distinct corticofugal neuron subtypes. Neuron 57, 232–247 (2008).
Alcamo, E.A. et al. Satb2 regulates callosal projection neuron identity in the developing cerebral cortex. Neuron 57, 364–377 (2008).
Britanova, O. et al. Satb2 is a postmitotic determinant for upper-layer neuron specification in the neocortex. Neuron 57, 378–392 (2008).
Joshi, P.S. et al. Bhlhb5 regulates the postmitotic acquisition of area identities in layers II–V of the developing neocortex. Neuron 60, 258–272 (2008).
Kwan, K.Y. et al. SOX5 postmitotically regulates migration, postmigratory differentiation and projections of subplate and deep-layer neocortical neurons. Proc. Natl. Acad. Sci. USA 105, 16021–16026 (2008).
Cobos, I. et al. Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nat. Neurosci. 8, 1059–1068 (2005).
Liodis, P. et al. Lhx6 activity is required for the normal migration and specification of cortical interneuron subtypes. J. Neurosci. 27, 3078–3089 (2007).
Zhao, Y. et al. Distinct molecular pathways for development of telencephalic interneuron subtypes revealed through analysis of Lhx6 mutants. J. Comp. Neurol. 510, 79–99 (2008).
Du, T., Xu, Q., Ocbina, P.J. & Anderson, S.A. NKX2.1 specifies cortical interneuron fate by activating Lhx6. Development 135, 1559–1567 (2008).
Butt, S.J. et al. The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes. Neuron 59, 722–732 (2008).
Smits, P. et al. The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev. Cell 1, 277–290 (2001).
Stolt, C.C. et al. SoxD proteins influence multiple stages of oligodendrocyte development and modulate SoxE protein function. Dev. Cell 11, 697–709 (2006).
Wegner, M. From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res. 27, 1409–1420 (1999).
Wegner, M. & Stolt, C.C. From stem cells to neurons and glia: a Soxist's view of neural development. Trends Neurosci. 28, 583–588 (2005).
Connor, F., Wright, E., Denny, P., Koopman, P. & Ashworth, A. The Sry-related HMG box-containing gene Sox6 is expressed in the adult testis and developing nervous system of the mouse. Nucleic Acids Res. 23, 3365–3372 (1995).
Narahara, M., Yamada, A., Hamada-Kanazawa, M., Kawai, Y. & Miyake, M. cDNA cloning of the Sry-related gene Sox6 from rat with tissue-specific expression. Biol. Pharm. Bull. 25, 705–709 (2002).
Puelles, L. et al. Pallial and subpallial derivatives in the embryonic chick and mouse telencephalon, traced by the expression of the genes Dlx-2, Emx-1, Nkx-2.1, Pax-6 and Tbr-1. J. Comp. Neurol. 424, 409–438 (2000).
Carney, R.S. et al. Cell migration along the lateral cortical stream to the developing basal telencephalic limbic system. J. Neurosci. 26, 11562–11574 (2006).
Ma, Q., Sommer, L., Cserjesi, P. & Anderson, D.J. Mash1 and neurogenin1 expression patterns define complementary domains of neuroepithelium in the developing CNS and are correlated with regions expressing notch ligands. J. Neurosci. 17, 3644–3652 (1997).
Scardigli, R., Baumer, N., Gruss, P., Guillemot, F. & Le Roux, I. Direct and concentration-dependent regulation of the proneural gene Neurogenin2 by Pax6. Development 130, 3269–3281 (2003).
Britz, O. et al. A role for proneural genes in the maturation of cortical progenitor cells. Cereb. Cortex 16 Suppl 1, i138–i151 (2006).
Batista-Brito, R., Machold, R., Klein, C. & Fishell, G. Gene expression in cortical interneuron precursors is prescient of their mature function. Cereb. Cortex 18, 2306–2317 (2008).
Tamamaki, N. et al. Green fluorescent protein expression and colocalization with calretinin, parvalbumin and somatostatin in the GAD67-GFP knock-in mouse. J. Comp. Neurol. 467, 60–79 (2003).
Cavanagh, M.E. & Parnavelas, J.G. Development of somatostatin immunoreactive neurons in the rat occipital cortex: a combined immunocytochemical-autoradiographic study. J. Comp. Neurol. 268, 1–12 (1988).
Cavanagh, M.E. & Parnavelas, J.G. Development of neuropeptide Y (NPY) immunoreactive neurons in the rat occipital cortex: a combined immunohistochemical-autoradiographic study. J. Comp. Neurol. 297, 553–563 (1990).
Vega, C.J. & Peterson, D.A. Stem cell proliferative history in tissue revealed by temporal halogenated thymidine analog discrimination. Nat. Methods 2, 167–169 (2005).
Holm, P.C. et al. Loss- and gain-of-function analyses reveal targets of Pax6 in the developing mouse telencephalon. Mol. Cell. Neurosci. 34, 99–119 (2007).
Molnár, Z. & Butler, A.B. The corticostriatal junction: a crucial region for forebrain development and evolution. Bioessays 24, 530–541 (2002).
Nóbrega-Pereira, S. et al. Postmitotic Nkx2-1 controls the migration of telencephalic interneurons by direct repression of guidance receptors. Neuron 59, 733–745 (2008).
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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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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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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DOI: https://doi.org/10.1038/nn.2387
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