The basic helix‐loop‐helix transcription factor TCF4 impacts brain architecture as well as neuronal morphology and differentiation

Abstract

Germline mutations in the basic helix‐loop‐helix transcription factor 4 (TCF4) cause the Pitt–Hopkins syndrome (PTHS), a developmental disorder with severe intellectual disability. Here, we report findings from a new mouse model with a central nervous system‐specific truncation of Tcf4 leading to severe phenotypic abnormalities. Furthermore, it allows the study of a complete TCF4 knockout in adult mice, circumventing early postnatal lethality of previously published mouse models. Our data suggest that a TCF4 truncation results in an impaired hippocampal architecture affecting both the dentate gyrus as well as the cornu ammonis. In the cerebral cortex, loss of TCF4 generates a severe differentiation delay of neural precursors. Furthermore, neuronal morphology was critically affected with shortened apical dendrites and significantly increased branching of dendrites. Our data provide novel information about the role of Tcf4 in brain development and may help to understand the mechanisms leading to intellectual deficits observed in patients suffering from PTHS.

Identifying Cattle Breed-Specific Partner Choice of Transcription Factors during the African Trypanosomiasis Disease Progression Using Bioinformatics Analysis

“…The factor TCF4 present in the network of N'Dama, belongs to a basic helix-loop-helix family which plays an integral role in Wnt signalling and neuronal differentiation especially in the brain development [146][147][148][149][150]. Furthermore, TCF4 is also involved in the immune responses through the production of plasmacytoid Dendritic Cells (pDCs), which respond to viral nucleic acids and autoimmune diseases, by the secretion of cytokines such as type I interferons [151][152][153][154].…”

Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

“…Adult-born neuron survival is highly dependent on maturation and synaptic integration (38)(39)(40). Recent studies reported that loss-of-Tcf4 causes delayed maturation of embryonically and early postnatally born neurons, impairs dendrite and synapse formation in the developing cortex (17,41), and decreases spine density of mature cortical and hippocampal neurons (42). When analysing the marker pro le of 4-week old adult-born neurons, we found that neurons in Tcf4Het mice less frequently displayed a mature marker pro le, which suggests the possibility that Tcf4 haploinsu ciency impaired maturation and thereby decreased survival of adult-born neurons.…”

“…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.…”

“…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).…”

Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

“…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.…”