A dual function of Bcl11b/Ctip2 in hippocampal neurogenesis

Simon, Ralph; Brylka, Heike; Schwegler, Herbert; Venkataramanappa, Sathish; Andratschke, Jacqueline; Wiegreffe, Christoph; Liu, Pentao; Fuchs, Elaine; Jenkins, Nancy A.; Copeland, Neal G.; Birchmeier, Carmen; Britsch, Stefan

doi:10.1038/emboj.2012.142

Cited by 104 publications

(166 citation statements)

References 57 publications

(87 reference statements)

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“…NeuroD is expressed in mitotic stages 2b/3 and early postmitotic cells 14 . We have shown previously that the number of NeuroD positive cells is significantly increased in Bcl11b conditional mutants indicating an arrest of neuronal differentiation 8 . While the number of GFP positive cells alone and GFP/NeuroD positive cells did not differ in control and mutant cells a significant increase in NeuroD positive cells was observed in the dentate gyrus where cells had received Cre recombinase ( Figure 2C; this figure has been modified from 8 ).…”

Section: Representative Resultsmentioning

confidence: 99%

“…We have shown previously that the number of NeuroD positive cells is significantly increased in Bcl11b conditional mutants indicating an arrest of neuronal differentiation 8 . While the number of GFP positive cells alone and GFP/NeuroD positive cells did not differ in control and mutant cells a significant increase in NeuroD positive cells was observed in the dentate gyrus where cells had received Cre recombinase ( Figure 2C; this figure has been modified from 8 ). Finding NeuroD positive cells not only in cells which had received Cre recombinase but also in wild-type cells suggested that indirect mechanisms are involved in Bcl11b regulation of neuronal cell differentiation.…”

Section: Representative Resultsmentioning

confidence: 99%

“…Furthermore mutant neurons fail to integrate into the hippocampal circuitry causing learning and memory impairment 8 . To answer questions concerning the regulatory mechanism(s) of Bcl11b in these processes ex utero electroporation was employed.…”

Section: Representative Resultsmentioning

confidence: 99%

“…Using mouse genetics and phenotype analysis by immunohistochemistry as well as molecular methods allowed defining the expression pattern and function of many of these genes. In addition microarray analysis as well as chromatin immunoprecipitation (ChIP) provided information about potential direct and indirect target genes 7,8 . However, there are still many open questions concerning the regulatory mechanisms of hippocampal development, in particular the development of the dentate gyrus.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to in utero electroporation not the whole embryo but only the head is used allowing therefore to place the electrodes in a more favorable way to direct the shRNA/DNA towards the hippocampus and dentate gyrus. Our group successfully employed ex utero electroporation to study the role of the transcription factor Bcl11b during dentate gyrus development 8 . Bcl11b has a dual role in dentate gyrus development by regulating progenitor cell proliferation as well as differentiation as was demonstrated by immunohistochemistry.…”

Section: Introductionmentioning

confidence: 99%

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<em>Ex Utero</em> Electroporation and Organotypic Slice Culture of Mouse Hippocampal Tissue

Venkataramanappa

Simon

Britsch

2015

JoVE

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Mouse genetics offers a powerful tool determining the role of specific genes during development. Analyzing the resulting phenotypes by immunohistochemical and molecular methods provides information of potential target genes and signaling pathways. To further elucidate specific regulatory mechanisms requires a system allowing the manipulation of only a small number of cells of a specific tissue by either overexpression, ablation or re-introduction of specific genes and follow their fate during development. To achieve this ex utero electroporation of hippocampal structures, especially the dentate gyrus, followed by organotypic slice culture provides such a tool. Using this system to generate mosaic deletions allows determining whether the gene of interest regulates cell-autonomously developmental processes like progenitor cell proliferation or neuronal differentiation. Furthermore it facilitates the rescue of phenotypes by re-introducing the deleted gene or its target genes. In contrast to in utero electroporation the ex utero approach improves the rate of successfully targeting deeper layers of the brain like the dentate gyrus. Overall ex utero electroporation and organotypic slice culture provide a potent tool to study regulatory mechanisms in a semi-native environment mirroring endogenous conditions. Video LinkThe video component of this article can be found at

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Section: Representative Resultsmentioning

confidence: 99%

Section: Representative Resultsmentioning

confidence: 99%

Section: Representative Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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<em>Ex Utero</em> Electroporation and Organotypic Slice Culture of Mouse Hippocampal Tissue

Venkataramanappa

Simon

Britsch

2015

JoVE

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Genes regulated by BCL11B during T‐cell development are enriched for de novo mutations found in schizophrenia patients

Fahey

Donohoe

Broin

et al. 2020

American J of Med Genetics Pt B

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While abnormal neurodevelopment contributes to schizophrenia (SCZ) risk, there is also evidence to support a role for immune dysfunction in SCZ. BCL11B, associated with SCZ in GWAS, is a transcription factor that regulates the differentiation and development of cells in the central nervous and immune systems. Here, we use functional genomics data from studies of BCL11B to investigate the contribution of neuronal and immune processes to SCZ pathophysiology. We identified the gene targets of BCL11B in brain striatal cells (n=223 genes), double negative 4 (DN4) developing T cells (n=114 genes) and double positive (DP) developing T cells (n=518 genes) using an integrated analysis of RNA-seq and ChIP-seq data. No gene-set was enriched for genes containing common variants associated with SCZ but the DP gene-set was enriched for genes containing missense de novo mutations (DNMs; P=0.001) using data from 3,447 SCZ trios. Post-hoc analysis revealed the enrichment to be stronger for DP genes negatively-regulated by BCL11B. Biological processes enriched for genes negatively-regulated by BCL11B in DP gene-set included immune system development and cytokine signaling. These analyses, leveraging a GWAS-identified SCZ risk gene and data on gene expression and transcription factor binding, indicate that DNMs in immune pathways contribute to SCZ risk.

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The role of BAF (mSWI/SNF) complexes in mammalian neural development

Son¹,

Crabtree²

2014

American J of Med Genetics Pt C

136

137

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The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in ES cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. The microRNA-mediated mechanism for transitioning from npBAF to nBAF complexes is instructive for the neuronal fate and can even convert fibroblasts into neurons. The high frequency of BAF subunit mutations in neurological disorders underscores the rate-determining role of BAF complexes in neural development, homeostasis and plasticity.

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A dual function of Bcl11b/Ctip2 in hippocampal neurogenesis

Abstract: The transcription factor Bcl11b/Ctip2 promotes hippocampal progenitor proliferation and neural differentiation in a non-cell autonomous manner by regulating the expression of the cell adhesion molecule Desmoplakin. Forebrain-specific ablation causes defective spatial learning and memory.

Cited by 104 publications

References 57 publications

<em>Ex Utero</em> Electroporation and Organotypic Slice Culture of Mouse Hippocampal Tissue

<em>Ex Utero</em> Electroporation and Organotypic Slice Culture of Mouse Hippocampal Tissue

Genes regulated by BCL11B during T‐cell development are enriched for de novo mutations found in schizophrenia patients

The role of BAF (mSWI/SNF) complexes in mammalian neural development

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