Knockdown of the schizophrenia susceptibility geneTCF4alters gene expression and proliferation of progenitor cells from the developing human neocortex.
Common variants in theTCF4gene are among the most robustly supported genetic risk factors for schizophrenia. RareTCF4deletions and loss-of-function point mutations cause Pitt-Hopkins syndrome, a developmental disorder associated with severe intellectual disability.



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.



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.



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



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.
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).
Matthew J
MJ
Hill
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).
Richard
R
Killick
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).
Katherinne
K
Navarrete
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).
Aleksandra
A
Maruszak
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).
Gemma M
GM
McLaughlin
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).
Brenda P
BP
Williams
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).
Nicholas J
NJ
Bray
D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D063990:Gene Ontology; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D046228:Microarray Analysis; D058953:Neural Stem Cells / Q000378:metabolism*; D034622:RNA Interference; D012559:Schizophrenia / Q000235:genetics; D000073940:Transcription Factor 4 / Q000172:deficiency* / Q000235:genetics
C532096:TCF4 protein, human; D000073940:Transcription Factor 4
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