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Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour.

Bacon C, Schneider M, Le Magueresse C, Froehlich H, Sticht C, Gluch C, Monyer H, Rappold GA - Mol. Psychiatry (2014)

Bottom Line: Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes.More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-Cre(Foxp1-/-) mice.Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Human Genetics, Medical Faculty of Heidelberg University, Im Neuenheimer Feld 366, Heidelberg, Germany [2] Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, Germany.

ABSTRACT
Neurodevelopmental disorders are multi-faceted and can lead to intellectual disability, autism spectrum disorder and language impairment. Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes. To understand the role of Foxp1 in the context of neurodevelopment leading to alterations in cognition and behaviour, we generated mice with a brain-specific Foxp1 deletion (Nestin-Cre(Foxp1-/-)mice). The mutant mice were viable and allowed for the first time the analysis of pre- and postnatal neurodevelopmental phenotypes, which included a pronounced disruption of the developing striatum and more subtle alterations in the hippocampus. More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-Cre(Foxp1-/-) mice. Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance.

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Morphological defects in the developing Foxp1 KO brain. Calbindin (a) and tyrosine hydroxylase (b) immunohistochemistry showing gross morphological disruption in the striatal region. Scale bar represents 1000 μm in adult brain sections, 500 μm in all others. (c) Quantification of the striatal region as defined by area of tyrosine hydroxylase positive staining, demonstrating a significant reduction in the striatum of Foxp1 KO brains, starting at P1. At least 12 sections from at least three WT and three KO brains were quantified for each stage. (d) Pathway analysis of microarray expression studies on P1 Foxp1 KO and WT striatal tissue showing the top 11 significantly regulated pathways.
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fig1: Morphological defects in the developing Foxp1 KO brain. Calbindin (a) and tyrosine hydroxylase (b) immunohistochemistry showing gross morphological disruption in the striatal region. Scale bar represents 1000 μm in adult brain sections, 500 μm in all others. (c) Quantification of the striatal region as defined by area of tyrosine hydroxylase positive staining, demonstrating a significant reduction in the striatum of Foxp1 KO brains, starting at P1. At least 12 sections from at least three WT and three KO brains were quantified for each stage. (d) Pathway analysis of microarray expression studies on P1 Foxp1 KO and WT striatal tissue showing the top 11 significantly regulated pathways.

Mentions: To determine whether loss of Foxp1 causes gross morphological abnormalities, we first performed Calbindin immunohistochemistry (Figure 1a) and Nissl stainings (Figure 2) on adult Foxp1 KO brains. A significant enlargement of the lateral ventricles in Foxp1 KO brains was observed (WT=0.00974 μ m−2; KO=0.0504 μ m−2, P-value (t test)=<0.0001; values represent lateral ventricle area normalised to the area of the whole brain), comparable with the magnetic resonance imaging scan of a patient with haploinsufficiency of FOXP1, which revealed prominent lateral ventricles.5 In addition, a striking reduction of the striatal region (Figures 1a, b and c) was observed. To investigate the striatal phenotype further, we stained the striatum of adult brains using tyrosine hydroxylase immunohistochemistry, which revealed a reduced dorsal striatum and an enlargement of the ventral region (Figure 1b). The distinction between the dorsal and ventral striatum is based on specific cortical, thalamic and dopaminergic inputs and is not defined by a distinct border.19 As no markers exist that uniquely characterise either region, we quantified the total striatal area (defined as the area of tyrosine hydroxylase positive staining), which was significantly smaller in Foxp1 KO brains compared with WT (Figure 1c).


Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour.

Bacon C, Schneider M, Le Magueresse C, Froehlich H, Sticht C, Gluch C, Monyer H, Rappold GA - Mol. Psychiatry (2014)

Morphological defects in the developing Foxp1 KO brain. Calbindin (a) and tyrosine hydroxylase (b) immunohistochemistry showing gross morphological disruption in the striatal region. Scale bar represents 1000 μm in adult brain sections, 500 μm in all others. (c) Quantification of the striatal region as defined by area of tyrosine hydroxylase positive staining, demonstrating a significant reduction in the striatum of Foxp1 KO brains, starting at P1. At least 12 sections from at least three WT and three KO brains were quantified for each stage. (d) Pathway analysis of microarray expression studies on P1 Foxp1 KO and WT striatal tissue showing the top 11 significantly regulated pathways.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4419151&req=5

fig1: Morphological defects in the developing Foxp1 KO brain. Calbindin (a) and tyrosine hydroxylase (b) immunohistochemistry showing gross morphological disruption in the striatal region. Scale bar represents 1000 μm in adult brain sections, 500 μm in all others. (c) Quantification of the striatal region as defined by area of tyrosine hydroxylase positive staining, demonstrating a significant reduction in the striatum of Foxp1 KO brains, starting at P1. At least 12 sections from at least three WT and three KO brains were quantified for each stage. (d) Pathway analysis of microarray expression studies on P1 Foxp1 KO and WT striatal tissue showing the top 11 significantly regulated pathways.
Mentions: To determine whether loss of Foxp1 causes gross morphological abnormalities, we first performed Calbindin immunohistochemistry (Figure 1a) and Nissl stainings (Figure 2) on adult Foxp1 KO brains. A significant enlargement of the lateral ventricles in Foxp1 KO brains was observed (WT=0.00974 μ m−2; KO=0.0504 μ m−2, P-value (t test)=<0.0001; values represent lateral ventricle area normalised to the area of the whole brain), comparable with the magnetic resonance imaging scan of a patient with haploinsufficiency of FOXP1, which revealed prominent lateral ventricles.5 In addition, a striking reduction of the striatal region (Figures 1a, b and c) was observed. To investigate the striatal phenotype further, we stained the striatum of adult brains using tyrosine hydroxylase immunohistochemistry, which revealed a reduced dorsal striatum and an enlargement of the ventral region (Figure 1b). The distinction between the dorsal and ventral striatum is based on specific cortical, thalamic and dopaminergic inputs and is not defined by a distinct border.19 As no markers exist that uniquely characterise either region, we quantified the total striatal area (defined as the area of tyrosine hydroxylase positive staining), which was significantly smaller in Foxp1 KO brains compared with WT (Figure 1c).

Bottom Line: Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes.More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-Cre(Foxp1-/-) mice.Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Human Genetics, Medical Faculty of Heidelberg University, Im Neuenheimer Feld 366, Heidelberg, Germany [2] Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, Germany.

ABSTRACT
Neurodevelopmental disorders are multi-faceted and can lead to intellectual disability, autism spectrum disorder and language impairment. Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes. To understand the role of Foxp1 in the context of neurodevelopment leading to alterations in cognition and behaviour, we generated mice with a brain-specific Foxp1 deletion (Nestin-Cre(Foxp1-/-)mice). The mutant mice were viable and allowed for the first time the analysis of pre- and postnatal neurodevelopmental phenotypes, which included a pronounced disruption of the developing striatum and more subtle alterations in the hippocampus. More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-Cre(Foxp1-/-) mice. Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance.

Show MeSH
Related in: MedlinePlus