Investigating the influence of imprinted Grb10 on brain growth

Sinha, Isadora 2025. Investigating the influence of imprinted Grb10 on brain growth. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Imprinted gene expression is enriched in the brain and is critical for growth and development. Imprinted genes usually have one universally silenced parental allele; this is not the case for Grb10. Paternal Grb10 is expressed in the brain, specifically in the mid and hind brain regions, whilst maternal Grb10 is expressed across other tissues. Previous research has found Grb10+/p brains are heavier. The nature and cause of this brain growth had not been determined. This thesis demonstrates that Grb10+/p adult mice have overgrown brains. Longitudinal MRI analysis showed that Grb10+/p mice have a significantly increased whole brain volume overall compared to Grb10m/+ and wildtypes. Therefore, the increased brain weight is attributable to an increase in volume rather than an increase in density. The rate of Grb10+/p brain growth is also significantly higher, with volumes between the Grb10+/p and control brains diverging further as time progressed. A BrdU assay and IHC was used to investigate proliferation and cell type proportions within the hippocampal formation (including the dentate gyrus) and subventricular zone. There were no differences found between Grb10+/p, Grb10m/+ and wildtype mice, aligning with previous findings. IHC and TEM were used to investigate oligodendrocytes, axon growth and myelination within the corpus callosum. There was no difference found between the number of oligodendrocytes in Grb10+/p and wildtype mice; there were fewer oligodendrocytes in Grb10m/+ mice. Genu TEM analysis revealed that Grb10+/p had a strong trend of larger axons compared to wildtype and an increased g-ratio, though not significant within the scope of this thesis. There was no difference found in myelin thickness; however, there appeared to be a decrease in the total number of (myelinated and unmyelinated) axons in Grb10+/p mice when measuring the same square area. This suggests that paternal Grb10 is a negative regulator of axon growth and may be involved in modulating myelination. Grb10 expression in StHdhQ7/7 cells was further validated, by microarray analysis and western blotting, for use in BioID.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	9 September 2025
Last Modified:	09 Sep 2025 08:51
URI:	https://orca.cardiff.ac.uk/id/eprint/180993

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