The intellectual disability and schizophrenia associated transcription factor TCF4 is regulated by neuronal activity and protein kinase A

Mari Sepp, Hanna Vihma, Kaja Nurm, Mari Urb, Stephanie Cerceo Page, Kaisa Roots, Anu Hark, Brady J. Maher, Priit Pruunsild, Tõnis Timmusk

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)10516-10527
Number of pages12
JournalJournal of Neuroscience
Volume37
Issue number43
DOIs
StatePublished - Oct 25 2017

Keywords

  • BHLH
  • E2-2
  • ITF2
  • Neuronal activity
  • Pitt-Hopkins syndrome
  • Schizophrenia

ASJC Scopus subject areas

  • Neuroscience(all)

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