Functional analysis of<i>TCF4</i>missense mutations that cause Pitt-Hopkins syndrome

Forrest, Marc P.; Chapman, Ria M.; Doyle, Aisling; Tinsley, Caroline L.; Waite, Adrian James; Blake, Derek J.

doi:10.1002/humu.22160

Cited by 68 publications

(54 citation statements)

References 47 publications

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“…This is exactly the opposite of what we observe with Da, where decreased Da leads to increased boutons and increased Da leads to decreased boutons (Figure 2). Further, human NRXN1 is a known transcriptional target of TCF4 in HEK293 cells (Forrest et al, 2012), and fly nrx-1 is a direct transcriptional target of Da in Drosophila embryos (MacArthur et al, 2009). Finally, TCF4 is associated with schizophrenia (Consortium, 2011; Stefansson et al, 2009; Steinberg et al, 2011), as is NRXN1 (Rujescu et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

Type I bHLH Proteins Daughterless and Tcf4 Restrict Neurite Branching and Synapse Formation by Repressing Neurexin in Postmitotic Neurons

et al. 2016

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Proneural proteins of the class I/II basic Helix Loop Helix (bHLH) family are highly conserved transcription factors. Class I bHLH proteins are expressed in a broad number of tissues during development, while class II bHLH protein expression is more tissue restricted. Our understanding of the function of class I/II bHLH transcription factors in both invertebrate and vertebrate neurobiology is largely focused on their function as regulators of neurogenesis. Here, we show that the class I bHLH proteins Daughterless and Tcf4 are expressed in postmitotic neurons in Drosophila melanogaster and mice, respectively, where they function to restrict neurite branching and synapse formation. Our data indicates that Daughterless performs this function in part by restricting the expression of the cell adhesion molecule Neurexin. This suggests a role for these proteins outside of their established roles in neurogenesis.

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Section: Resultsmentioning

confidence: 99%

Type I bHLH Proteins Daughterless and Tcf4 Restrict Neurite Branching and Synapse Formation by Repressing Neurexin in Postmitotic Neurons

et al. 2016

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“…Initial examination of the most robust gene expression changes in TCF4-knockdown cells (Figure 2A) appeared to suggest a role for TCF4 in apoptosis or inflammasome function (up-regulation of CASP1 and CASP4 ), cell signaling (down-regulation of IGF2 , BMP7 and LEFTY1 ) and neurodevelopment (down-regulation of NEUROG2 , ASCL1 and MEF2C ). Furthermore, several of the major gene expression changes in TCF4-knockdown cells involved transcription factors including ASCL1 and NEUROG2 that interact directly with TCF4 at E-boxes [6,10,11,25]. Finally, a number of imprinted genes, IGF2 , H19 and CDKN1C were prominent amongst the most significantly downregulated genes in TCF4-knockdown cells (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

Knockdown of Human TCF4 Affects Multiple Signaling Pathways Involved in Cell Survival, Epithelial to Mesenchymal Transition and Neuronal Differentiation

et al. 2013

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Haploinsufficiency of TCF4 causes Pitt-Hopkins syndrome (PTHS): a severe form of mental retardation with phenotypic similarities to Angelman, Mowat-Wilson and Rett syndromes. Genome-wide association studies have also found that common variants in TCF4 are associated with an increased risk of schizophrenia. Although TCF4 is transcription factor, little is known about TCF4-regulated processes in the brain. In this study we used genome-wide expression profiling to determine the effects of acute TCF4 knockdown on gene expression in SH-SY5Y neuroblastoma cells. We identified 1204 gene expression changes (494 upregulated, 710 downregulated) in TCF4 knockdown cells. Pathway and enrichment analysis on the differentially expressed genes in TCF4-knockdown cells identified an over-representation of genes involved in TGF-β signaling, epithelial to mesenchymal transition (EMT) and apoptosis. Among the most significantly differentially expressed genes were the EMT regulators, SNAI2 and DEC1 and the proneural genes, NEUROG2 and ASCL1. Altered expression of several mental retardation genes such as UBE3A (Angelman Syndrome), ZEB2 (Mowat-Wilson Syndrome) and MEF2C was also found in TCF4-depleted cells. These data suggest that TCF4 regulates a number of convergent signaling pathways involved in cell differentiation and survival in addition to a subset of clinically important mental retardation genes.

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“…As for the case of the known TCF4 target genes CNTNAP2 and NRXN1 [76], which are mutated in an autosomal-recessive manner to cause Pitt-Hopkins-like syndrome 1 and 2, respectively [77], identification of the other CNS targets of TCF4 may also help elucidate a better understanding of convergent pathophysiology and related clinical syndromes. For this, it will be necessary to comprehensively identify the full set of TCF4 target genes, taking into account the many isoforms of TCF4 (different isoforms may regulate different target genes), as well as brain cell type-specific factors (TCF4 may target different genes in different brain cell types).…”

Section: Discussionmentioning

confidence: 99%

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

et al. 2017

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Genetic variation within the transcription factor TCF4 locus can cause the intellectual disability and developmental disorder Pitt-Hopkins syndrome (PTHS), whereas single-nucleotide polymorphisms within noncoding regions are associated with schizophrenia. These genetic findings position TCF4 as a link between transcription and cognition; however, the neurobiology of TCF4 remains poorly understood. Here, we quantitated multiple distinct TCF4 transcript levels in human induced pluripotent stem cell-derived neural progenitors and differentiated neurons, and PTHS patient fibroblasts. We identify two classes of pharmacological treatments that regulate TCF4 expression: WNT pathway activation and inhibition of class I histone deacetylases. In PTHS fibroblasts, both of these perturbations upregulate a subset of TCF4 transcripts. Finally, using chromatin immunoprecipitation sequencing in conjunction with genome-wide transcriptome analysis, we identified TCF4 target genes that may mediate the effect of TCF4 loss on neuroplasticity. Our studies identify new pharmacological assays, tools, and targets for the development of therapeutics for cognitive disorders.

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Functional analysis ofTCF4missense mutations that cause Pitt-Hopkins syndrome

Cited by 68 publications

References 47 publications

Type I bHLH Proteins Daughterless and Tcf4 Restrict Neurite Branching and Synapse Formation by Repressing Neurexin in Postmitotic Neurons

Type I bHLH Proteins Daughterless and Tcf4 Restrict Neurite Branching and Synapse Formation by Repressing Neurexin in Postmitotic Neurons

Knockdown of Human TCF4 Affects Multiple Signaling Pathways Involved in Cell Survival, Epithelial to Mesenchymal Transition and Neuronal Differentiation

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

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