Synaptic gene DLG2 contributes to cortical interneuron development

Ghazwani, Asmaa 2022. Synaptic gene DLG2 contributes to cortical interneuron development. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Several genetic as well as environmental factors have been identified concerning schizophrenia (SCZ). For example, the uncommon deletion of the gene, DLG2, has been observed in numerous individuals suffering from SCZ. This gene encodes a structural scaffolding protein found in fully developed synapses. For exploring DLG2’s proposed function concerning early inhibitory cortical development and establishing this gene’s possible relevance to pathological manifestations, wild-type (WT) and DLG2-/- human embryonic stem cell (hESC) lines underwent differentiation into cortical inhibitory interneurons. Their properties were observed at numerous time points using various methods. The present study implies that DLG2 protein is expressed earlier than currently believed and before synaptic development in cortical interneurons. Further, DLG2’s novel functions during cortical interneuron development were identified, such as the neural progenitor cell gene expression governance and the extracellular matrix’s (ECM) adherence. Also, some altered biological processes identified through single-cell RNA sequencing (scRNAseq) concerned the regulation of translational initiation, DNA transcription and initiation, RNA splicing and regulation of chromosome organization. The DLG2-/- gene set was not enriched for SCZ common risk variants. Nonetheless, analysing WT DEGs for a link with SCZ common risk variants showed that the developing neuronal cell subtype was associated with SCZ regardless of DLG2’s contribution. A greater frequency of immature neuronal cells was induced in DLG2-/- cultures, typified by aberrations in migration, morphology, and protein expression, such as for the transcription factors, NKX2.1 and OLIG2. Embryonic mice brains were used to determine the murine interneurons’ properties that were homozygous or heterozygous for Dlg2. Heterozygous brains showed patterns of diminishing proportions of CGE COUPTF2+ cells, whereas homozygous brains showed decreasing frequencies of NKX2.1 and COUPTF2 positive cells. Combining all in vitro and in vivo observations, DLG2 significantly contributes to interneuron development/birth, maturation, differentiation, and migratory characteristics.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	20 December 2022
Last Modified:	19 Dec 2023 02:30
URI:	https://orca.cardiff.ac.uk/id/eprint/155028

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