Weir, Emma Jane
2025.
Using patient-specific stem cells to interrogate the role of oligodendrocytes in 1q21.1 duplication.
PhD Thesis,
Cardiff University.
Item availability restricted. |
![]() |
PDF (PhD thesis)
- Accepted Post-Print Version
Restricted to Repository staff only until 29 September 2026 due to copyright restrictions. Download (8MB) |
![]() |
PDF (Cardiff University Electronic Publication Form)
- Supplemental Material
Restricted to Repository staff only Download (70kB) |
Abstract
Copy number variants associated with neurodevelopmental disorders (NDD-CNVs) provide a unique opportunity to investigate the genetic mechanisms driving neurodevelopmental and mental health disorders. Structural chromosomal alterations frequently exacerbate pathophysiological effects, making them valuable in dissecting mechanisms that contribute to atypical brain development linked to clinical phenotypes. 1q21.1 distal duplication is a rare, recurrent CNV spanning approximately 1.35 Mb on chromosome 1 and involving ~12 genes. The CNV has been linked to increased incidence of autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and intellectual disability (ID), as well as other non-neurological phenotypes. Previous studies have established that 1q21.1 duplication disrupts neuronal development and maturation, and emerging research suggests that these CNVs may also influence white matter. However, the specific influence of 1q21.1 duplication in oligodendrocyte (OL) development and myelination remains unexplored. To unravel the underlying oligodendrocyte pathophysiology, this thesis investigates the impact of 1q21.1 duplication on white matter development using patient-derived induced pluripotent stem cells (iPSCs) differentiated into 2D oligodendrocyte cultures and advanced 3D “oligo-organoids” containing myelin. It demonstrates that 1q21.1 duplication significantly disrupts oligodendrocyte development in both 2D cultures and 3D oligo-organoids. In the oligo-organoids, myelination deficits were accompanied by abnormalities in neuronal development, reduced functional activity, and impaired network connectivity. Notably, 1q21.1 duplication models revealed an increased population of oligodendrocyte progenitors, hinting at a developmental bottleneck or compensatory response. To investigate potential therapeutic approaches to rescue dysmyelination, pro-myelinating drugs were evaluated for their ability to address OL developmental deficits. Benzatropine was found to significantly accelerate oligodendrocyte maturation in 1q21.1 duplication organoids. This work is the first to examine the impact of 1q21.1 duplication on oligodendroglial development in a 3D model integrating both oligodendrocyte and neuronal development. The findings highlight the potential of enhancing developmental myelination as a promising therapeutic strategy for neurodevelopmental disorders linked to 1q21.1 duplication.
Item Type: | Thesis (PhD) |
---|---|
Date Type: | Completion |
Status: | Unpublished |
Schools: | Schools > Biosciences |
Subjects: | Q Science > Q Science (General) |
Date of First Compliant Deposit: | 16 September 2025 |
Last Modified: | 29 Sep 2025 12:59 |
URI: | https://orca.cardiff.ac.uk/id/eprint/181109 |
Actions (repository staff only)
![]() |
Edit Item |