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Generation and characterisation of human embryonic stem cells deficient in ZDHHC8, a gene deleted in 22q11.2 deletion syndrome

Trigano, Matthieu 2017. Generation and characterisation of human embryonic stem cells deficient in ZDHHC8, a gene deleted in 22q11.2 deletion syndrome. PhD Thesis, Cardiff University.
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The 22q11.2 Deletion Syndrome is caused by a deletion on the chromosome 22q11.2. Individuals carrying 22q11.2 deletion have an increased risk to develop schizophrenia and Parkinson disease. However, how this deletion leads to the development of these diseases and the specific role of the individual 22q11.2 genes remains largely unknown. In order to understand the neuronal cell types and developmental stages in which the 22q11.2 genes may function, we investigated the temporal and spatial expression profile of the genes located in the 22q11.2DS by RT-PCR. Human embryonic stem cells (hESCs) was used to generate excitatory projection neurons, cortical interneurons, GABAergic medium spiny neurons (MSN) and dopaminergic neurons. This study revealed that several genes appear to exhibit a specific temporal expression profile. Moreover, another group of genes were found to be preferentially expressed in dopaminergic neural lineage. Within the 22q11.2 deletion region, ZDHHC8 is an interesting candidate due to its implication in the physiology and morphology of the neurons. I generated a hESCs cellular model carrying a heterozygous deletion of ZDHHC8. These cells can be induced toward cortical projection neuron fate in a comparable temporal kinetics to that of the parental control cells. However, phenotypic characterisation revealed that ZDHHC8 mutation altered the motility and the spontaneous calcium activity in ZDHHC8+/- neurons. Interestingly, transcriptomic analysis of excitatory progenitors identified altered expression of genes regulating calcium activity and axonal growth (motility). Furthermore, this study suggests that ZDHHC8 may also be involved in neuronal development, patterning and synaptic signalling. In conclusion, this thesis provides further knowledges regarding the expression of the 22q11.2DS genes which would be valuable to guide future studies either in cellular or animal models. Furthermore, this study indicates that ZDHHC8 function is involved in several aspects of neuron development that potentially plays a role in the aetiology of 22q11.2DS.

Item Type: Thesis (PhD)
Date Type: Submission
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 10 April 2018
Last Modified: 20 May 2021 14:56

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