The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A
| Autor: | Kaja Nurm, Stephanie Cerceo Page, Mari Sepp, Hanna Vihma, Tõnis Timmusk, Brady J. Maher, Anu Hark, Priit Pruunsild, Kaisa Roots, Mari Urb |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Journal Club Biology Hippocampus Rats Sprague-Dawley 03 medical and health sciences Transcription Factor 4 Transcription (biology) Intellectual Disability Transcriptional regulation Premovement neuronal activity Animals Humans Amino Acid Sequence Protein kinase A education Transcription factor Cells Cultured Cerebral Cortex Neurons education.field_of_study General Neuroscience TCF4 Soluble adenylyl cyclase Cyclic AMP-Dependent Protein Kinases 3. Good health Rats DNA-Binding Proteins 030104 developmental biology HEK293 Cells GADD45G Schizophrenia Female Neuroscience Transcription Factors |
| Zdroj: | The Journal of Neuroscience |
| ISSN: | 1529-2401 |
| Popis: | 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 brainin vivo. We also demonstrate thatGadd45g(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.SIGNIFICANCE STATEMENTThe 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. |
| Databáze: | OpenAIRE |
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