The Journal of neuroscience, 2017-10, Vol.37 (43), p.10516-10527
2017
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- Autor(en) / Beteiligte
- Titel
- The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A
- Ist Teil von
- The Journal of neuroscience, 2017-10, Vol.37 (43), p.10516-10527
- Ort / Verlag
- United States: Society for Neuroscience
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0270-6474eISSN: 1529-2401DOI: 10.1523/JNEUROSCI.1151-17.2017Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5656997
- Format
- –
- Schlagworte
- Amino Acid Sequence, Animals, Brain, Cells, Cultured, Cerebral Cortex - metabolism, Cognitive ability, Cyclic AMP-Dependent Protein Kinases - genetics, Cyclic AMP-Dependent Protein Kinases - metabolism, Deoxyribonucleic acid, DNA, DNA damage, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Embryos, Female, Gene regulation, HEK293 Cells, Helix-loop-helix proteins (basic), Hippocampus - metabolism, Humans, Intellectual disabilities, Intellectual Disability - genetics, Intellectual Disability - metabolism, Kinases, Male, Mental disorders, Neurons, Neurons - metabolism, Phosphorylation, Protein kinase A, Proteins, Rats, Rats, Sprague-Dawley, Schizophrenia, Schizophrenia - genetics, Schizophrenia - metabolism, Transcription Factor 4, Transcription factors, Transcription Factors - genetics, Transcription Factors - metabolism