A systems level approach to identify and validate imprinted genes involved in parental care and the associated neural circuitry

Higgs, Matthew 2022. A systems level approach to identify and validate imprinted genes involved in parental care and the associated neural circuitry. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Imprinted genes are primarily associated with prenatal biology but have also been shown to substantially impact the post-natal brain and, its output, infant and adult behaviour. One behaviour classically associated with genomic imprinting is maternal care. Maternal care, and parenting more generally, is an essential behaviour in mammals in order to keep offspring alive who are unable to care for themselves and is controlled by a highly conserved neural circuit centred in the medial preoptic area (MPOA) of the hypothalamus. The mechanism by which imprinted genes influence parenting behaviour is mostly unknown and recent findings have cast doubt on the prior research which established a relationship between these genes and parenting in the first place. Using a systems level approach, this thesis first analysed a set of single cell RNA sequencing (sc-RNA seq) datasets from the mouse body and brain, analysing in which tissues, regions and cell types, a set of imprinted genes would show enrichment. I hypothesized that, given their relationship to parenting, preoptic area neurons might be one of the enriched areas for imprinted genes. The results of this first study showed that imprinted genes do show enrichment in specific areas of the mouse brain, and one of those regions was the parenting associated neurons of the preoptic area, neurons expressing galanin (Gal), tyrosine hydroxylase (Th) and calcitonin receptor (Calcr). This produced a list of 21 imprinted genes contributing to the enrichment in these neurons. These genes represented potential candidates for involvement in parenting behaviour and suggested that imprinted genes may converge on this function as a gene set. To validate this approach, one of the 21 genes was selected for further study, making up the rest of this thesis. Magel2 was selected as the candidate gene, a paternally expressed gene with no previously characterised parenting deficits. I confirmed that Magel2 was enriched in Gal/Calcr expressing neurons before finding that mothers, fathers and virgin females, null for Magel2, displayed parenting deficits in retrieval, nest building and pup-directed attention. Finally, I showed that Magel2-null mothers have reduced activity in the Preoptic Area (POA) following exposure to pups and substantial reduction in galanin expression in the POA. Together, I have found a novel imprinted gene associated with parenting, Magel2, and a mechanism by which Magel2, and perhaps other imprinted genes, could regulate parenting behaviour, by modulating the neuroendocrine ability of galanin expressing neurons.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	21 April 2023
Last Modified:	21 Apr 2023 13:56
URI:	https://orca.cardiff.ac.uk/id/eprint/158979

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