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

Molecular Psychiatry volume 24, pages 1235–1246 (2019)Cite this article

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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.

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Acknowledgements

We thank Mariamma Pappy for technical help and Brian Rash for helpful discussions and Ruth Rappaport, Ph.D. for editing the manuscript. We are grateful to the Kavli Institute for Neuroscience at Yale and the National Institutes of Health for NIH funding: DA02399; EY002593; NS014841 (PR) and National Natural Science Foundation of China: #81471159 (HL).

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Authors and Affiliations

  1. Department of Neuroscience, Yale University School of Medicine, New Haven, CT, 06510, USA

    Hong Li, Yury M. Morozov & Pasko Rakic

  2. School of Basic Medical Sciences, Anhui Medical University, Anhui, China

    Hong Li

  3. Biopharmaceutical Institute, Anhui Medical University, Anhui, China

    Hong Li

  4. Department of Biostatistics, School of Public Health, Yale University, New Haven, CT, 06510, USA

    Ying Zhu

  5. Department of Medical Genetics, Capital Institute of Pediatrics, 100020, Beijing, China

    Xiaoli Chen

  6. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA

    Stephanie Cerceo Page, Matthew D. Rannals & Brady J. Maher

  7. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    Brady J. Maher

  8. Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    Brady J. Maher

  9. Kavli Institute for Neuroscience, Yale University, New Haven, CT, 06510, USA

    Pasko Rakic

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Li, H., Zhu, Y., Morozov, Y.M. et al. Disruption of TCF4 regulatory networks leads to abnormal cortical development and mental disabilities. Mol Psychiatry 24, 1235–1246 (2019). https://doi.org/10.1038/s41380-019-0353-0

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