Tcf4 is required for correct brain development during embryogenesis

Mesman, Simone; Bakker, Reinier; Smidt, Marten P.

doi:10.1016/j.mcn.2020.103502

Cited by 40 publications

(53 citation statements)

References 78 publications

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“…2020), which underlines the importance of TCF-4 in establishing interhemispheric 288 connectivity. In contrast to our study, Mesman and colleagues found subtle defects in 289 midline formation (Mesman et al 2020). These phenotypic differences may be 290 Our approach of gene regulatory network analysis enabled us to identify how TCF-4 316 may affect these downstream targets.…”

Section: Disorders 243contrasting

confidence: 99%

“…explained by the different genetic setup of the respective Tcf4KO models. While the 291 present Tcf4KO model allowed for the residual expression of shorter TCF-4 isoforms 292 with a functional bHLH domain, the Tcf4 KO strain analysed byMesman and 293 colleagues harboured a mutation that removed the DNA binding bHLH domain from 294 all isoforms(Mesman et al 2020). Hence, future studies should address to what 295 extent different TC-F4 isoforms contribute to the development of the midline.…”

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confidence: 96%

“…Hence, future studies should address to what 295 extent different TC-F4 isoforms contribute to the development of the midline. 296Bulk RNA-Sequencing analyses of the developing murine neocortex of Tcf4KO mice 297 showed that TCF-4 regulates a diverse set of genes with functions in cell 298 proliferation, neuronal differentiation, and neurotransmitter release(Li et al 2019; 299 Mesman et al 2020), which reflects TCF4's pleiotropic functions in cortical 300 development(Li et al 2019;Mesman et al 2020; Page et al 2017). However, given 301 the broad expression of TCF4(Jung et al 2018) and the considerable cellular 302 diversity in the developing neocortex, bulk RNA-Sequencing data is not ideally suited 303 to molecularly explain the complex phenotype of Tcf4KO mice and to identify cell-304 type and or stage-specific TCF-4 dependent mechanisms.…”

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confidence: 99%

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scRNA-Sequencing uncovers a TCF-4-dependent transcription factor network regulating commissure development

Wittmann

Kirchner

Ekici

et al. 2020

Preprint

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3Intercortical connectivity is important for higher cognitive brain functions by providing 4 the basis for integrating information from both hemispheres. We show that ablation of 5 the neurodevelopmental disorder associated bHLH factor Tcf4 results in complete 6 loss of forebrain commissural systems in mice. Applying a new bioinformatic strategy 7 integrating transcription factor expression levels and regulon activities from single cell 8 RNA-sequencing data predicted a TCF-4 interacting transcription factor network in 9 intercortical projection neurons regulating commissure formation. This network 10 comprises a number of regulators previously linked to the pathogenesis of intellectual 11 disability, autism-spectrum disorders and schizophrenia, e.g. Foxg1, Sox11 and 12Brg1. Furthermore, we demonstrate that TCF-4 and SOX11 biochemically interact 13 and cooperatively control commissure formation in vivo, and regulate the 14 transcription of genes implied in this process. Our study provides a regulatory 15 transcriptional network for the development of interhemispheric connectivity with 16 potential pathophysiological relevance in neurodevelopmental disorders. 17 18 19 mice is associated with callosal dysgenesis indicating that Tcf4 is part of a conserved 53 genetic network controlling the formation of callosal connections (Jung et al. 2018). 54 TCF-4 belongs to the class I basic basic Helix-Loop-Helix (bHLH) transcription factor 55 family and its transcriptional output is highly dependent on its interaction partners. 56Traditionally, it is assumed that TCF-4 executes its function through dimerization with 57 proneural class II bHLH TFs (Bertrand et al. 2002;Massari and Murre 2000). A 58 recent in vitro study, however, proposed that TCF-4 may be able to interact with a 59 variety of transcriptional regulators outside of the traditional interaction partners of the 60 bHLH class (Moen et al. 2017). TCF-4-interacting transcription factors in the 61 regulation of interhemispheric connectivity have not been identified. Such 62 identification is hampered by the technical challenges to perform unbiased in vivo 63interactome analyses in a cell type specific manner. 64Here, we generated homozygote Tcf4 knockout (Tcf4KO) mice to further validate the 65 role of TCF-4 in the establishment of interhemispheric connectivity. We report that 66 loss of Tcf4 results in the complete agenesis of forebrain commissures. Using single-67 cell RNA sequencing (scRNA-seq) followed by the integration of transcription factor 68 expression levels and regulon activities we uncover a TCF-4 interacting transcription 69 factor network for commissure development in Satb2 expressing neurons. 70Surprisingly, this transcription factor network involves numerous transcription factors 71 outside the bHLH class. Similar to TCF-4, these interactors are often associated to 72 neurodevelopmental disorders such as intellectual disability, autism and 73 schizophrenia. Further analysis of the interaction between TCF-4 and the regulator 74 SOX11 uncovered a syner...

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Section: Disorders 243contrasting

confidence: 99%

mentioning

confidence: 96%

mentioning

confidence: 99%

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scRNA-Sequencing uncovers a TCF-4-dependent transcription factor network regulating commissure development

Wittmann

Kirchner

Ekici

et al. 2020

Preprint

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“…In rodents, TCF4 controls proliferation of cortical precursor cells, balances precursor proliferation versus differentiation, regulates fate choices and migration, and modulates dendrite and spine development (14)(15)(16)(17)(18). Loss of Tcf4 causes imbalanced generation of deep vs. upper layer neurons, delays neuronal differentiation, and impairs dendritogenesis and synapse formation (14,17,19). Development of the hippocampal formation appears to be particularly reliant on precise TCF4 dosage.…”

Section: Introductionmentioning

confidence: 99%

“…MR-analyses uncovered small hippocampi in individuals with PTHS (13,20). Heterozygote Tcf4 knockout mice show a signi cant reduction in hippocampal volume (13), while homozygote TCF4 knockout mice and transgenic mice with a homozygote embryonic neural stem cell speci c-deletion of TCF4 show severe hippocampal hypoplasia (12,17,19). TCF4 is also highly expressed in the adult brain (13), and is thought to have critical function in the regulation of neural plasticity (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

Braun

Häberle

Wittmann

et al. 2020

Preprint

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Background: Transcription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life.Results: We here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice.Conclusion:The present findings indicate that haploinsufficiency for the intellectual disability- and PTHS-linked transcription factor TCF4 not only affects embryonic neurodevelopment but impedes neurogenesis in the hippocampus of adult mice. These findings suggest that TCF4 haploinsufficiency may have a negative impact on hippocampal function throughout adulthood by impeding hippocampal neurogenesis.

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Analysis of the Relationship between Genetic Factors and the Risk of Schizophrenia

Shmakova,

Semina,

Neyfeld

et al. 2023

Neurosci Behav Physi

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Tcf4 is required for correct brain development during embryogenesis

Cited by 40 publications

References 78 publications

scRNA-Sequencing uncovers a TCF-4-dependent transcription factor network regulating commissure development

scRNA-Sequencing uncovers a TCF-4-dependent transcription factor network regulating commissure development

Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

Analysis of the Relationship between Genetic Factors and the Risk of Schizophrenia

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