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Title: The function of TCF4 in Pitt-Hopkins syndrome and schizophrenia
Author: Forrest, Marc
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2013
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Genome-wide association studies have identified TCF4 (transcription factor 4) as a susceptibility gene for schizophrenia. In addition, rare TCF4 mutations cause Pitt Hopkins syndrome (PTHS), a severe form of intellectual disability associated with characteristic facial features, developmental delay and autonomic dysfunction. TCF4 belongs to the basic helix-loop-helix family (bHLH) of transcription factors that play a central role in development, however the precise function of this gene in the brain is unknown. In this study, I use molecular and cellular techniques to improve our understanding of TCF4 function in the brain. Modeling of PTHS-associated missense mutations in transfected cells showed that TCF4 mutations affecting the DNA-binding domain cause mislocalisation of the mutant protein. DNA-binding domain mutations also impaired dimerisation and attenuated transcriptional activity at the NRXN1 and CNTNAP2 promoters. TCF4 mutations affecting other domains of the protein had context-specific deficits in dimerisation and transactivation under the same conditions. Microarray analysis of SH-SY5Y cells where all TCF4 isoforms had been knocked down identified gene expression changes affecting cellular processes including epithelial-to-mesenchymal transition, apoptosis and neurodevelopment. However, isoform-specific knockdown experiments showed that TCF4-A and TCF4-B isoforms affect distinct biological processes such as the cell cycle, chromatin modification (TCF4-B), cell adhesion and cytoskeletal remodeling (TCF4-A). Finally, mass spectrometry was used to identify TCF4-associated proteins in SHSY5Y cells. These experiments showed that TCF4-B and TCF4-A co-purified with proteins involved in chromatin organization, cell cycle control and RNA splicing. In addition to the bHLH factors HAND2 and TWIST2, TCF4 co-purified with components of the nuclear co-repressor complex. TCF4 also has multiple phosphorylation sites in both activation domains suggesting that TCF4 function may be regulated by kinase signaling. In conclusion, these data provide a mechanistic insight into the function of TCF4 that may advance our understanding of disease processes in PTHS and schizophrenia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry