Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neocortex

Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neocortex

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J Psychiatry Neurosci 2017;42(3):181-188

Matthew J. Hill, PhD; Richard Killick, PhD; Katherinne Navarrete, PhD; Aleksandra Maruszak, PhD; Gemma M. McLaughlin, MSc; Brenda P. Williams, PhD; Nicholas J. Bray, PhD

Abstract

Background: Common variants in the TCF4 gene are among the most robustly supported genetic risk factors for schizophrenia. Rare TCF4 deletions and loss-of-function point mutations cause Pitt–Hopkins syndrome, a developmental disorder associated with severe intellectual disability.

Methods: To explore molecular and cellular mechanisms by which TCF4 perturbation could interfere with human cortical development, we experimentally reduced the endogenous expression of TCF4 in a neural progenitor cell line derived from the developing human cerebral cortex using RNA interference. Effects on genome-wide gene expression were assessed by microarray, followed by Gene Ontology and pathway analysis of differentially expressed genes. We tested for genetic association between the set of differentially expressed genes and schizophrenia using genome-wide association study data from the Psychiatric Genomics Consortium and competitive gene set analysis (MAGMA). Effects on cell proliferation were assessed using high content imaging.

Results: Genes that were differentially expressed following TCF4 knockdown were highly enriched for involvement in the cell cycle. There was a nonsignificant trend for genetic association between the differentially expressed gene set and schizophrenia. Consistent with the gene expression data, TCF4 knockdown was associated with reduced proliferation of cortical progenitor cells in vitro.

Limitations: A detailed mechanistic explanation of how TCF4 knockdown alters human neural progenitor cell proliferation is not provided by this study.

Conclusion: Our data indicate effects of TCF4 perturbation on human cortical progenitor cell proliferation, a process that could contribute to cognitive deficits in individuals with Pitt–Hopkins syndrome and risk for schizophrenia.


Submitted Apr. 15, 2016; Revised Aug. 1, 2016; Accepted Aug. 31, 2016; Early-released Oct. 4, 2016

Acknowledgements: This work was supported by the Medical Research Council, UK [Grant ID: G0802166]. The authors are grateful to ReNeuron Ltd for providing the human neural cell line used in this study and to The Genome Centre, Barts and The London School of Medicine and Dentistry for microarray analysis.

Affiliations: From the Department of Basic and Clinical Neuroscience, King’s College London, London, UK (Hill, Killick, Maruszak, McLaughlin, Williams, Bray); the MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK (Navarrete); Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK (Hill); and the MRC Centre for Neuropsychiatric Genetics & Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK (Bray).

Competing interests: None declared.

Contributors: M. Hill, B. Williams and N. Bray designed the study. M. Hill, R. Killick, K. Navarrete, A. Maruszak and G. McLaughlin acquired and analyzed the data, which N. Bray also analyzed. N. Bray wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.160073

Correspondence to: N. Bray, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University School of Medicine, Cardiff, UK; brayN3@Cardiff.ac.uk.