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 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)
JournalMolecular Psychiatry
DOIs
StatePublished - Jan 1 2019

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Genes
Haploinsufficiency
Neocortex
Neurogenesis
Locomotion
Embryonic Stem Cells
Autistic Disorder
Dendrites
Transcriptome
Neuroglia
Synapses
Introns
Cognition
Gestational Age
Schizophrenia
Up-Regulation
Learning
Depression
Neurons
Research

ASJC Scopus subject areas

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

Cite this

Disruption of TCF4 regulatory networks leads to abnormal cortical development and mental disabilities. / Li, Hong; Zhu, Ying; Morozov, Yury M.; Chen, Xiaoli; Page, Stephanie Cerceo; Rannals, Matthew D.; Maher, Brady; Rakic, Pasko.

In: Molecular Psychiatry, 01.01.2019.

Research output: Contribution to journalArticle

Li, Hong ; Zhu, Ying ; Morozov, Yury M. ; Chen, Xiaoli ; Page, Stephanie Cerceo ; Rannals, Matthew D. ; Maher, Brady ; Rakic, Pasko. / Disruption of TCF4 regulatory networks leads to abnormal cortical development and mental disabilities. In: Molecular Psychiatry. 2019.
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