The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A

Abstract

Transcription factor 4 (TCF4 also known as ITF2 or E2-2) is a basic helix-loop-helix (bHLH) protein associated with Pitt-Hopkins syndrome, intellectual disability, and schizophrenia (SCZ). Here, we show that TCF4-dependent transcription in cortical neurons cultured from embryonic rats of both sexes is induced by neuronal activity via soluble adenylyl cyclase and protein kinase A (PKA) signaling. PKA phosphorylates TCF4 directly and a PKA phosphorylation site in TCF4 is necessary for its transcriptional activity in cultured neurons and in the developing brain We also demonstrate that (growth arrest and DNA damage inducible gamma) is a direct target of neuronal-activity-induced, TCF4-dependent transcriptional regulation and that TCF4 missense variations identified in SCZ patients alter the transcriptional activity of TCF4 in neurons. This study identifies a new role for TCF4 as a neuronal-activity-regulated transcription factor, offering a novel perspective on the association of TCF4 with cognitive disorders. The importance of the basic helix-loop-helix transcription factor transcription factor 4 (TCF4) in the nervous system is underlined by its association with common and rare cognitive disorders. In the current study, we show that TCF4-controlled transcription in primary cortical neurons is induced by neuronal activity and protein kinase A. Our results support the hypotheses that dysregulation of neuronal-activity-dependent signaling plays a significant part in the etiology of neuropsychiatric and neurodevelopmental disorders.

The Fuchs corneal dystrophy-associated CTG repeat expansion in the TCF4 gene affects transcription from its alternative promoters

“…Different TCF4 transcripts encode for various TCF4 protein isoforms (Fig. 1 B) that vary in their function and transactivation capability 4 , 8 . The major TCF4 transcripts comprising of 5′ exons 3b, 3c and 3d encode for isoform TCF4-B when spliced to internal exon 3; transcripts with exons 3b and 3d encode for isoform TCF4-C when spliced to exon 4; transcripts with exons 8a, 8bII and 8cII encode for isoform TCF4-D when spliced to exon 8; transcripts with exons 10a, 10b and 10c spliced to exon 10 encode for isoforms TCF4-A, TCF4-I and TCF4-H, respectively (Fig.…”

“…We have previously shown that TCF4 protein isoforms can be divided into longer and shorter isoforms which vary in their function and transactivation capability 4 , 8 . Currently FECD research focuses mainly on the CTG TNR and missplicing of longer TCF4 transcripts in FECD 17 , and little research has been done to analyze the expression of all the TCF4 transcripts in FECD.…”

“…In the brain TCF4 expression peaks during late embryonic development and continues at a relatively high level during postnatal development 6 , 7 . Notably, transcription from TCF4 gene can begin at multiple mutually exclusive 5′ exons leading to transcripts with varying composition of functional protein domains which modulate the ability of TCF4 to regulate transcription 4 , 8 .…”

Generation of 10 patient-specific induced pluripotent stem cells (iPSCs) to model Pitt-Hopkins Syndrome

“…TCF4 regulates many important functions during cortical development including neural progenitor proliferation, lineage commitment, neuronal migration, columnar organization, neurite outgrowth and myelination ( Li et al, 2019 ; Page et al, 2018 ; Phan et al, 2020 ). In addition, TCF4 appears to be an activity-dependent transcription factor that is capable of responding to neuronal activity while also regulating neuronal activity ( Page et al, 2018 ; Rannals et al, 2016 ; Sepp et al, 2017 ).…”

Potentially repurposable drugs for schizophrenia identified from its interactome

“…88 Within purview of the fact that defects in myelination is a pathological marker of schizophrenia, this is interesting because two rare mutations (G428V and P299S) found in TCF4 that were associated with schizophrenia have been found to have increased transcriptional activity of TCF4 and in another study, density of mature oligodendrocytes essential for myelination have been observed to be reduced in white matter derived from prefrontal cortex of schizophrenia patients, which is an expected outcome if TCF4, a negative modulator of mature oligodendrocytes were to be overexpressed. [90][91][92] Also, treatment with DRD2/DRD3 agonist, quinpirole, has shown a decrease in the number of mature oligodendrocytes while treatment with haloperidol, a DRD2 antagonist, has shown an increase in the number of mature oligodendrocytes. 93 Many studies have noted this interplay of myelination and dopaminergic systems.…”