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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 disrupts the normal laminar position and morphology of cortical interneurons. Analysis of GAD67-GFP mice reveals that, while there are equal numbers of cortical interneurons at P0 (a) and P14 (b) in WT and Sox6−/− cortex, there is a redistribution of interneurons toward deeper cortical layers in Sox6−/− cortex compared to WT (c,d). Quantification at P0 (c) reveals a proportional increase in interneuron density in the deepest bin 1 by 13% (p = 0.01) and bin 2 by 5% (p = 0.04), and a proportional decrease in more superficial bin 3 by 7% (p = 0.05) and bin 4 by 10% (p = 0.004). Quantification at P14 (d) reveals an increase in interneuron density in the deepest bin 1 by 10% (p = 0.001) and a decrease in the more superficially located bin 3 by 5% (p = 0.0003). Red lines (a,b) indicate subdivision into 4 bins for quantification (see Methods). Interneurons have abnormal tangential morphology in Sox6−/− cortex compared to the radially oriented interneurons in WT cortex (a; red arrowheads). (a,b) immunocytochemistry. WT, wildtype; MZ, marginal zone; CP, cortical plate; WM, white matter. Dotted lines (a,b) indicate pial surface. Scale bars, (a; low magnification) 200 μm, (a; intermediate magnification) 50 μm, (a; high magnification) 25 μm, (b; low magnification) 300 μm, (b; high magnification) 100 μm. Results are expressed as the mean ± SEM.
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Figure 5: Loss of SOX6 function disrupts the normal laminar position and morphology of cortical interneurons. Analysis of GAD67-GFP mice reveals that, while there are equal numbers of cortical interneurons at P0 (a) and P14 (b) in WT and Sox6−/− cortex, there is a redistribution of interneurons toward deeper cortical layers in Sox6−/− cortex compared to WT (c,d). Quantification at P0 (c) reveals a proportional increase in interneuron density in the deepest bin 1 by 13% (p = 0.01) and bin 2 by 5% (p = 0.04), and a proportional decrease in more superficial bin 3 by 7% (p = 0.05) and bin 4 by 10% (p = 0.004). Quantification at P14 (d) reveals an increase in interneuron density in the deepest bin 1 by 10% (p = 0.001) and a decrease in the more superficially located bin 3 by 5% (p = 0.0003). Red lines (a,b) indicate subdivision into 4 bins for quantification (see Methods). Interneurons have abnormal tangential morphology in Sox6−/− cortex compared to the radially oriented interneurons in WT cortex (a; red arrowheads). (a,b) immunocytochemistry. WT, wildtype; MZ, marginal zone; CP, cortical plate; WM, white matter. Dotted lines (a,b) indicate pial surface. Scale bars, (a; low magnification) 200 μm, (a; intermediate magnification) 50 μm, (a; high magnification) 25 μm, (b; low magnification) 300 μm, (b; high magnification) 100 μm. Results are expressed as the mean ± SEM.

Mentions: To further investigate whether the molecular and migratory irregularities in early stages of Sox6−/− subpallial neuron differentiation are associated with abnormalities in subsequent stages of interneuron cortical invasion, we examined the laminar location and morphology of these interneurons as they populate the cortex. In GAD67-GFP mice at P0 (Fig. 5a), just after the interneurons have begun their radial migration into the maturing cortex, as well as at P14 (Fig. 5b), as they have more fully adopted their mature phenotypes, Sox6−/− interneurons preferentially populate deeper neocortical layers (Fig. 5c,d), without any change in their total numbers. (Although the large majority of Sox6−/− mice die perinatally, small numbers survive a few weeks postnatally, allowing P14 analysis32. Sox6+/− mice survive to adulthood, though a small number exhibit occasional seizure behavior.) In examining the morphology of GAD67-GFP+ neurons at P0, in contrast to the mostly radial orientation of wildtype interneurons (reflecting their transition from tangential to radial migration), Sox6−/− interneurons display abnormal, tangential orientation (Fig. 5a). These laminar distribution and morphological abnormalities are confirmed by analysis of the broad (at P0) interneuron marker calbindin (Calb) (Supplementary Fig. 6a). These data indicate that SOX6 plays a critical role in the differentiation of cortical interneurons as they integrate into the neocortical circuitry, manifested by their inappropriately deep laminar location and abnormal morphology.


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 disrupts the normal laminar position and morphology of cortical interneurons. Analysis of GAD67-GFP mice reveals that, while there are equal numbers of cortical interneurons at P0 (a) and P14 (b) in WT and Sox6−/− cortex, there is a redistribution of interneurons toward deeper cortical layers in Sox6−/− cortex compared to WT (c,d). Quantification at P0 (c) reveals a proportional increase in interneuron density in the deepest bin 1 by 13% (p = 0.01) and bin 2 by 5% (p = 0.04), and a proportional decrease in more superficial bin 3 by 7% (p = 0.05) and bin 4 by 10% (p = 0.004). Quantification at P14 (d) reveals an increase in interneuron density in the deepest bin 1 by 10% (p = 0.001) and a decrease in the more superficially located bin 3 by 5% (p = 0.0003). Red lines (a,b) indicate subdivision into 4 bins for quantification (see Methods). Interneurons have abnormal tangential morphology in Sox6−/− cortex compared to the radially oriented interneurons in WT cortex (a; red arrowheads). (a,b) immunocytochemistry. WT, wildtype; MZ, marginal zone; CP, cortical plate; WM, white matter. Dotted lines (a,b) indicate pial surface. Scale bars, (a; low magnification) 200 μm, (a; intermediate magnification) 50 μm, (a; high magnification) 25 μm, (b; low magnification) 300 μm, (b; high magnification) 100 μm. Results are expressed as the mean ± SEM.
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Figure 5: Loss of SOX6 function disrupts the normal laminar position and morphology of cortical interneurons. Analysis of GAD67-GFP mice reveals that, while there are equal numbers of cortical interneurons at P0 (a) and P14 (b) in WT and Sox6−/− cortex, there is a redistribution of interneurons toward deeper cortical layers in Sox6−/− cortex compared to WT (c,d). Quantification at P0 (c) reveals a proportional increase in interneuron density in the deepest bin 1 by 13% (p = 0.01) and bin 2 by 5% (p = 0.04), and a proportional decrease in more superficial bin 3 by 7% (p = 0.05) and bin 4 by 10% (p = 0.004). Quantification at P14 (d) reveals an increase in interneuron density in the deepest bin 1 by 10% (p = 0.001) and a decrease in the more superficially located bin 3 by 5% (p = 0.0003). Red lines (a,b) indicate subdivision into 4 bins for quantification (see Methods). Interneurons have abnormal tangential morphology in Sox6−/− cortex compared to the radially oriented interneurons in WT cortex (a; red arrowheads). (a,b) immunocytochemistry. WT, wildtype; MZ, marginal zone; CP, cortical plate; WM, white matter. Dotted lines (a,b) indicate pial surface. Scale bars, (a; low magnification) 200 μm, (a; intermediate magnification) 50 μm, (a; high magnification) 25 μm, (b; low magnification) 300 μm, (b; high magnification) 100 μm. Results are expressed as the mean ± SEM.
Mentions: To further investigate whether the molecular and migratory irregularities in early stages of Sox6−/− subpallial neuron differentiation are associated with abnormalities in subsequent stages of interneuron cortical invasion, we examined the laminar location and morphology of these interneurons as they populate the cortex. In GAD67-GFP mice at P0 (Fig. 5a), just after the interneurons have begun their radial migration into the maturing cortex, as well as at P14 (Fig. 5b), as they have more fully adopted their mature phenotypes, Sox6−/− interneurons preferentially populate deeper neocortical layers (Fig. 5c,d), without any change in their total numbers. (Although the large majority of Sox6−/− mice die perinatally, small numbers survive a few weeks postnatally, allowing P14 analysis32. Sox6+/− mice survive to adulthood, though a small number exhibit occasional seizure behavior.) In examining the morphology of GAD67-GFP+ neurons at P0, in contrast to the mostly radial orientation of wildtype interneurons (reflecting their transition from tangential to radial migration), Sox6−/− interneurons display abnormal, tangential orientation (Fig. 5a). These laminar distribution and morphological abnormalities are confirmed by analysis of the broad (at P0) interneuron marker calbindin (Calb) (Supplementary Fig. 6a). These data indicate that SOX6 plays a critical role in the differentiation of cortical interneurons as they integrate into the neocortical circuitry, manifested by their inappropriately deep laminar location and abnormal morphology.

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