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The proteolytic processing and nuclear function of Protocadherin-19

Newbold, Sylvia Adriana 2021. The proteolytic processing and nuclear function of Protocadherin-19. PhD Thesis, Cardiff University.
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Abstract

Mutations in the X-linked gene PCDH19 lead to epilepsy with cognitive impairment in heterozygous females and post-zygotic mosaic males. The disorder phenotype is currently explained by cellular mosaicism of PCDH19 expressing and non-expressing PCDH19 cells in the brain, which leads to defective cell-cell communication and circuits. Although the gene codes for a cell adhesion protein belonging the cadherin superfamily localized at the cell membrane, recent reports have implicated PCDH19 in the regulation of gene expression and have identified the protein in the nucleus. Despite this, the nuclear function of PCDH19 in neurons and the potential proteolytic processing of PCDH19 have not been investigated yet. This thesis focussed on the proteolytic processing of PCDH19 as a potential mechanism of membrane-to-nucleus signalling in neurons. mESC-derived neurons were used to test the involvement of different proteases in the processing of PCDH19 and it was established that PCDH19 can undergo activity-dependent proteolysis. As the cytoplasmic domain of PCDH19 was found to localise to the nucleus, the nuclear function of the generated fragment was investigated. To determine potential transcriptional targets of the PCDH19 cytoplasmic domain, a mouse embryonic stem cell line that overexpresses the cytoplasmic domain of PCDH19 from the Rosa26 locus (PCDH19-CYTO), and an isogenic PCDH19-knockout line (PCDH19-KO) were generated. The transcriptional profile of embryonic stem cell-derived progenitors and neurons was obtained via RNA sequencing. The results of the analysis suggest a role for the cytoplasmic domain of PCDH19 in modulating expression of genes related to neuronal circuit assembly and synaptic function. Further analysis will be necessary to determine the relevance of these findings in the context of PCDH19-epilepsy.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > Q Science (General)
Funders: Wellcome Trust
Date of First Compliant Deposit: 1 October 2021
Last Modified: 03 May 2022 13:45
URI: https://orca.cardiff.ac.uk/id/eprint/144599

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