@article{d4057c33f37b4ad6bd4a881d8e8fb6b2,
title = "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 in vivo. We also demonstrate that Gadd45g (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.",
keywords = "BHLH, E2-2, ITF2, Neuronal activity, Pitt-Hopkins syndrome, Schizophrenia",
author = "Mari Sepp and Hanna Vihma and Kaja Nurm and Mari Urb and Page, {Stephanie Cerceo} and Kaisa Roots and Anu Hark and Maher, {Brady J.} and Priit Pruunsild and T{\~o}nis Timmusk",
note = "Funding Information: ThisworkwassupportedbyEstonianResearchCouncil(institutionalresearchfundingIUT19-18Grants7257and 8844), the National R&D program “Health” (Grant AR12098), the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) and H2020-MSCA-RISE-2016 (EU734791), the Estonian AcademyofSciences,andthePittHopkinsResearchFoundationandMillionDollarBikeRidePilotGrantProgramfor Rare Disease Research at UPenn Orphan Disease Center (Grants MDBR-16-122-PHP and MDBR-17-127-Pitt Hopkins). B.J.M. was supported by the Lieber Institute of the National Institutes of Health (Grant R56MH104593), the National Institutes of Health (Grant R01MH110487), a NARSAD Young Investigator Award, and a Pitt Hopkins Research Foundation Award. We thank Indrek Koppel for constructive discussions and critical reading of the manuscript; Epp V{\"a}li and Maila R{\"a}hn for technical assistance; Buket Basmanav for sharing data about TCF4 mutations in szhizophrenia patients; and Hilmar Bading for pRV1, pH21, pFdelta6, and rAAV-U6-shRNA-mCherry constructs. The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2017 the authors.",
year = "2017",
month = oct,
day = "25",
doi = "10.1523/JNEUROSCI.1151-17.2017",
language = "English (US)",
volume = "37",
pages = "10516--10527",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "43",
}