CYFIP1-dependent regulatory networks during cortical differentiation of human pluripotent stem cells: Implications in neuropsychiatric diseases

Cabezas De La Fuente, Daniel 2019. CYFIP1-dependent regulatory networks during cortical differentiation of human pluripotent stem cells: Implications in neuropsychiatric diseases. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Copy number variants affecting the chromosomic locus ch15q11.2 are associated with an increased risk for the development of neuropsychiatric disorders. CYFIP1 is one of the four genes within the 15q11.2 region and is the most studied thus far. While multiple studies have demonstrated a role for CYFIP1 in the physiology and morphology of neuronal cells, how altered expression of CYFIP1 and the other 15q11.2 genes confer risk to neuropsychiatric disorders remain largely unknown. Increased levels of CYFIP1 caused a delayed in neurogenesis while decreased levels caused the progenitor cells to prematurely differentiate into neural cells.This thesis investigates the transcriptional changes associated with altered levels of CYFIP1 in order to elucidate the mechanisms behind the observed cellular phenotypes. RNAseq analysis revealed altered overlapping pathways in these cells that could explain the observed phenotype. This also revealed new functions associated with CYFIP1-regulated genes involving mitochondrial and cholesterol metabolism. Common variant analysis indicated that amongst the CYFIP1-regulated genes, those that are targets of FMRP show a significant enrichment for genetic variants conferring increased risk for schizophrenia. In-depth analysis indicated that AKT3 was one of the top candidate genes involved in the development of the abnormal phenotype observed in cells with altered CYFIP1 expression. Genetic manipulation of ATK3 using a lentiviral CRISPR/Cas9 system showed evidence that AKT3 is involved, in part, in the maintenance of the neural progenitor cells in CYFIP1tg cultures. This thesis demonstrates that the defects caused by altered CYFIP1 expression can be explained partly by changes in AKT3 activity elucidating a potential mechanism behind the neuropsychiatric phenotype associated with 15q11.2 CNVs.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	17 February 2020
Last Modified:	29 Mar 2021 14:02
URI:	https://orca.cardiff.ac.uk/id/eprint/129646

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