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SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development.

Azim E, Jabaudon D, Fame RM, Macklis JD - Nat. Neurosci. (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Massachusetts General Hospital-Harvard Medical School Center for Nervous System Repair, Harvard Medical School, Boston, Massachusetts, USA.

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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Loss of SOX6 function results in abnormal early cortical interneuron differentiation, without a change in interneuron number. (a) While excitatory neuron-specific Vglut2 is not normally expressed in neurons born in the subpallium, shown here at E15.5 (red arrowheads), in Sox6−/− mice, Vglut2 is ectopically expressed in the subpallial mantle zone. (b,c) GAD67-GFP+ neurons are born in both wildtype and Sox6−/− MGE (white arrowheads). However, as GABAergic cortical interneurons tangentially migrate into the cortex, the leading edge of the marginal zone (MZ) migratory stream is consistently less advanced in the Sox6−/− cortex compared to wildtype (white arrows) (60% reduction in distance; p = 0.03 (c)). (d) There is no difference between wildtype and Sox6−/− cortex in the number of migrating cortical interneurons in either the MZ or IZ/SVZ migratory streams. (a) in situ hybridization; (b) immunocytochemistry. WT, wildtype; MZ, marginal zone; IZ, intermediate zone; SVZ, subventricular zone. Dotted lines (b) indicate lateral ventricle boundary. Scale bars, (a; low magnification) 150 μm, (a; high magnification, b; low magnification) 100 μm, (b; high magnification) 50 μm. Results are expressed as the mean ± SEM.
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Figure 4: Loss of SOX6 function results in abnormal early cortical interneuron differentiation, without a change in interneuron number. (a) While excitatory neuron-specific Vglut2 is not normally expressed in neurons born in the subpallium, shown here at E15.5 (red arrowheads), in Sox6−/− mice, Vglut2 is ectopically expressed in the subpallial mantle zone. (b,c) GAD67-GFP+ neurons are born in both wildtype and Sox6−/− MGE (white arrowheads). However, as GABAergic cortical interneurons tangentially migrate into the cortex, the leading edge of the marginal zone (MZ) migratory stream is consistently less advanced in the Sox6−/− cortex compared to wildtype (white arrows) (60% reduction in distance; p = 0.03 (c)). (d) There is no difference between wildtype and Sox6−/− cortex in the number of migrating cortical interneurons in either the MZ or IZ/SVZ migratory streams. (a) in situ hybridization; (b) immunocytochemistry. WT, wildtype; MZ, marginal zone; IZ, intermediate zone; SVZ, subventricular zone. Dotted lines (b) indicate lateral ventricle boundary. Scale bars, (a; low magnification) 150 μm, (a; high magnification, b; low magnification) 100 μm, (b; high magnification) 50 μm. Results are expressed as the mean ± SEM.

Mentions: Because MGE and CGE Sox6−/− mantle zone cells ectopically Ngn2, which normally represses subpallial and maintains pallial identity4, we hypothesized that these cells might abnormally initiate pallium-like gene expression. Consistent with this hypothesis, Sox6−/− subpallial mantle zone cells inappropriately express Vglut2, a vesicular glutamate transporter, whose expression is normally restricted to pallium-born excitatory projection neurons (Fig. 4a). This indicates that at least a subpopulation of Sox6−/− subpallial immature neurons in the mantle zone are inappropriately differentiating.


SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development.

Azim E, Jabaudon D, Fame RM, Macklis JD - Nat. Neurosci. (2009)

Loss of SOX6 function results in abnormal early cortical interneuron differentiation, without a change in interneuron number. (a) While excitatory neuron-specific Vglut2 is not normally expressed in neurons born in the subpallium, shown here at E15.5 (red arrowheads), in Sox6−/− mice, Vglut2 is ectopically expressed in the subpallial mantle zone. (b,c) GAD67-GFP+ neurons are born in both wildtype and Sox6−/− MGE (white arrowheads). However, as GABAergic cortical interneurons tangentially migrate into the cortex, the leading edge of the marginal zone (MZ) migratory stream is consistently less advanced in the Sox6−/− cortex compared to wildtype (white arrows) (60% reduction in distance; p = 0.03 (c)). (d) There is no difference between wildtype and Sox6−/− cortex in the number of migrating cortical interneurons in either the MZ or IZ/SVZ migratory streams. (a) in situ hybridization; (b) immunocytochemistry. WT, wildtype; MZ, marginal zone; IZ, intermediate zone; SVZ, subventricular zone. Dotted lines (b) indicate lateral ventricle boundary. Scale bars, (a; low magnification) 150 μm, (a; high magnification, b; low magnification) 100 μm, (b; high magnification) 50 μm. Results are expressed as the mean ± SEM.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2903203&req=5

Figure 4: Loss of SOX6 function results in abnormal early cortical interneuron differentiation, without a change in interneuron number. (a) While excitatory neuron-specific Vglut2 is not normally expressed in neurons born in the subpallium, shown here at E15.5 (red arrowheads), in Sox6−/− mice, Vglut2 is ectopically expressed in the subpallial mantle zone. (b,c) GAD67-GFP+ neurons are born in both wildtype and Sox6−/− MGE (white arrowheads). However, as GABAergic cortical interneurons tangentially migrate into the cortex, the leading edge of the marginal zone (MZ) migratory stream is consistently less advanced in the Sox6−/− cortex compared to wildtype (white arrows) (60% reduction in distance; p = 0.03 (c)). (d) There is no difference between wildtype and Sox6−/− cortex in the number of migrating cortical interneurons in either the MZ or IZ/SVZ migratory streams. (a) in situ hybridization; (b) immunocytochemistry. WT, wildtype; MZ, marginal zone; IZ, intermediate zone; SVZ, subventricular zone. Dotted lines (b) indicate lateral ventricle boundary. Scale bars, (a; low magnification) 150 μm, (a; high magnification, b; low magnification) 100 μm, (b; high magnification) 50 μm. Results are expressed as the mean ± SEM.
Mentions: Because MGE and CGE Sox6−/− mantle zone cells ectopically Ngn2, which normally represses subpallial and maintains pallial identity4, we hypothesized that these cells might abnormally initiate pallium-like gene expression. Consistent with this hypothesis, Sox6−/− subpallial mantle zone cells inappropriately express Vglut2, a vesicular glutamate transporter, whose expression is normally restricted to pallium-born excitatory projection neurons (Fig. 4a). This indicates that at least a subpopulation of Sox6−/− subpallial immature neurons in the mantle zone are inappropriately differentiating.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Massachusetts General Hospital-Harvard Medical School Center for Nervous System Repair, Harvard Medical School, Boston, Massachusetts, USA.

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.

Show MeSH
Related in: MedlinePlus