Modelling of neurodevelopmental disorders associated with 1q21.1 deletion and duplication using human iPSCs

Chapman, Gareth 2019. Modelling of neurodevelopmental disorders associated with 1q21.1 deletion and duplication using human iPSCs. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Copy number variation at the 1q21.1 locus (both deletion and duplication) has been associated with a wide variety of neurological phenotypes including changes in brain size and increased risk for developing psychiatric disorders. Deletion of the 1q21.1 locus is primarily associated with an increased risk of schizophrenia whereas duplication of the same locus is primarily associated with an increased risk of autism. These mutations present an untapped opportunity to understand the cellular deficits which underly both common and specific risk for psychiatric disorders. Patient derived iPSCs were made from individuals carrying either 1q21.1 deletion or duplication and were then used to model both neuronal and oligodendrocyte development. The presence of 1q21.1 CNVs was associated with significant changes in neuronal and oligodendroglial development. Deletion of the 1q21.1 locus was associated with increased neuronal activity and a reduced production of mature oligodendrocytes. On the other hand, duplication of the 1q21.1 locus was associated with deficits in the production of neurons and specification of oligodendrocytes. Key findings from the iPSC models were also validated using a 1q21.1 microdeletion mouse model and human brain imaging data from 1q21.1 carriers. These results constitute the first examination of human cellular dysfunction associated with copy number variation at the 1q21.1 locus. Furthermore, this work clearly demonstrates the importance of examining the effect of mutations on both glial and neuronal cells. To develop a system which could provide further insight into the interactions between these two cell types this study also examined the feasibility of bioprinting, as a technique for 3D cell culture. Using iPSC derived astrocytes and neurons a novel alginate based bioink was developed which could support the short-term maintenance of both cell types. Therefore, demonstrating that 3D bioprinting is a viable technique for generating 3D culture systems for iPSC derived neuronal cells.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	14 May 2020
Last Modified:	14 May 2021 02:05
URI:	https://orca.cardiff.ac.uk/id/eprint/131675

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