Disruption of TCF4 regulatory networks leads to abnormal cortical development and mental disabilities

Hong Li, Ying Zhu, Yury M. Morozov, Xiaoli Chen, Stephanie Cerceo Page, Matthew D. Rannals, Brady J. Maher, Pasko Rakic

Research output: Contribution to journalArticle

Abstract

The TCF4 gene is the subject of numerous and varied investigations of it’s role in the genesis of neuropsychiatric disease. The gene has been identified as the cause of Pitt–Hopkins syndrome (PTHS) and it has been implicated in various other neuropsychiatric diseases, including schizophrenia, depression, and autism. However, the precise molecular mechanisms of the gene’s involvement in neurogenesis, particularly, corticogenesis, are not well understood. Here, we present data showing that TCF4 is expressed in a region-specific manner in the radial glia and stem cells of transient embryonic zones at early gestational ages in both humans and mice. TCF4 haploinsufficiency mice exhibit a delay in neuronal migration, and a significant increase in the number of upper-layer cortical neurons, as well as abnormal dendrite and synapse formation. Our research also reveals that TCF3 up-regulates Tcf4 by binding to the specific “E-box” and its flank sequence in intron 2 of the Tcf4 gene. Additionally, our transcriptome study substantiates that Tcf4 transcriptional function is essential for locomotion, cognition, and learning. By activating expression of TCF4 in the regulation of neuronal proliferation and migration to the overlaying neocortex and subsequent differentiation leading to laminar formation TCF4 fulfills its normal function, but if not, abnormalities such as those reported here result. These findings provide new insight into the specific roles of Tcf4 molecular pathway in neocortical development and their relevance in the pathogenesis of neuropsychiatric diseases.

Original languageEnglish (US)
Pages (from-to)1235-1246
Number of pages12
JournalMolecular psychiatry
Volume24
Issue number8
DOIs
StatePublished - Aug 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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