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Molecular mechanisms of PCDH19 regulation of neurogenesis

Fox, Ian William John 2023. Molecular mechanisms of PCDH19 regulation of neurogenesis. PhD Thesis, Cardiff University.
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The neurons that compose the mammalian cerebral cortex are born from a seemingly uniform population of progenitor cells through a process called “cortical neurogenesis”. This process is strictly regulated to ensure progenitors produce neurons at the right time and in correct numbers, and defects in neurogenesis are linked to neurological disorders. Mutations in the X-linked gene protocadherin-19 (PCDH19) lead to PCDH19-epilepsy, a disorder that causes early onset epilepsy and cognitive impairment. Although the disease mechanism is unknown, PCDH19 tissue mosaicism is thought to be a crucial underlying factor. Recent work at the Isabel Martinez-Garay (IMG) lab has suggested that the presence of PCDH19 in neural progenitor cells may be important for regulating cortical neurogenesis. Progenitors that expressed either the wildtype (WT) or knockout (KO) PCDH19 allele showed delayed and premature neurogenesis, respectively. Interestingly, this only occurred in the developing brain of heterozygous (HET) mice, since homozygous WT and KO animals showed normal neurogenesis rates. This thesis aimed to examine the molecular mechanisms by which PCDH19 may regulate cortical neurogenesis. To identify molecular hallmarks by which PCDH19 may regulate neurogenesis, bulk RNA-seq and single cell (sc)RNA-seq were performed on cortical tissue from WT, HET, and KO embryonic day (E)11 animals. The bulk RNA-seq initially found few differentially expressed (DE) genes between mutant and WT same sex counterparts. However, enrichment analyses suggested several pathways were upregulated in HET and KO animals, including pathways related to ribosomes, BMP signalling, and Wnt signalling. The results from the scRNA-seq analysis revealed numerous DE genes between mutants and WTs when examined within cell clusters of interest (progenitors and excitatory neurons), including genes related to neurogenesis, Wnt signalling, and Shh signalling. Interestingly, HETs also displayed a marked reduction in ribosomal gene expression compared to WTs and KOs. However, one of the most striking findings from this analysis was that despite WT and KO cells within the HET animals displaying altered neurogenesis rates, no DE genes were uncovered between these cells when compared to each other, suggesting they are transcriptionally similar. Data was also generated that revealed a role of PCDH19 in negatively modulating Wnt signalling, potentially through an interaction with β-catenin and the noncanonical Wnt receptor, RYK. Moreover, immunostaining using pLRP6 antibodies revealed no differences in the proportion of pLRP6 cells in HETs, however KO animals showed a slightly increased proportion. Taken together, this thesis provides the first examination of the molecular mechanisms of PCDH19 in cortical development. The transcriptional data generated will help direct future work to unravel the role of PCDH19 as a regulator of neurogenesis.

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: 3 August 2023
Last Modified: 03 Aug 2023 12:14

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