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Paternal Grb10 in brain and behaviour

Rienecker, Kira 2018. Paternal Grb10 in brain and behaviour. PhD Thesis, Cardiff University.
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Abstract

Imprinted genes are highly expressed in the brain and have a role in adult behaviour. Additionally, madumnal and padumnal genomes contribute disproportionately to certain brain regions. Previous research has shown paternal Grb10 is expressed in mid and hind brain regions, with high expression in monoaminergic systems, and is not expressed in the cortex. This thesis demonstrates Grb10+/p mouse brains are overgrown in both weight and volume, and their postnatal allometry differs from wildtype and Grb10+/m controls. Using longitudinal MRI, I found both cortical and subcortical volumes are larger in Grb10+/p than wildtypes, in contrast previous studies using Nisslstaining, which reported overgrowth only in subcortical regions. I also used IHC to investigate total cell and neuronal counts in the caudate putamen, where paternal Grb10 is expressed, and found no difference between Grb10+/p and wildtype brains. Grb10+/p male mice are also reported to have enhanced social dominance. I next investigated social dominance behaviours to determine if their emergence or severity correlated with brain allometry. We found Grb10+/p mice of both sexes were no more likely to win social dominance encounters under social housing conditions. Under social isolation stress, Grb10+/p males were less likely to win (in contrast to previously published work), while Grb10+/p females were more likely to win. We also found no consistent correlation in cage rank measured by social tube test, urine marking, and barbering. This suggests Grb10+/p mice may display a social instability phenotype, and begs comparison to Cdkn1cBACx1 mice. Finally, I constructed a CRISPR/dCas9 based epigenome editor to make targeted changes to the imprinting control region for functional studies. These tools will aid causal studies of imprinting regulatory mechanisms and will avoid the problems associated with classical approaches such as direct manipulation of the DNA sequence (deletion studies) or widespread manipulation of epigenetic readers, writers, erasers, and marks.

Item Type: Thesis (PhD)
Date Type: Submission
Status: Unpublished
Schools: Medicine
Last Modified: 25 Jul 2019 02:05
URI: http://orca.cf.ac.uk/id/eprint/118838

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