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Title: Interacting functions of reciprocally expressed imprinted transcripts from the mouse Gnas locus
Author: Dickins, B. J. A.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2007
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Gnas encodes Gsα, the alpha subunit of the stimulatory G protein, and Gnasxl encodes XLαs, an N-terminally extended form of Gsα. A splice variant of the latter gives rise to a C-terminally truncated, brain-specific protein known as XLN1a. Posited functional antagonism between these isoforms (Gsα versus XLαs and versus XLN1a) was investigated using two strategies. In the first (chapter two) loss of maternal and paternal function in one animal was achieved by means of a di-allelic intercross between Gnas exon 2 null and Gnasxl first exon null mice. Compound heterozygote offspring, lacking both maternal Gnas and paternal Gnasxl, were contrasted with littermates lacking only one transcript (maternal or paternal heterozygotes) for a range of postnatal and adult physiological phenotypes. Rescue effects relative to both single heterozygote classes were observed in compound heterozygotes for phenotypes such as survival to weaning. Several phenotypes also exhibited subtle changes over time indicating complex interactions between transcripts. Most phenotypes, however, showed epistatic outcomes in which the effects of Gnasxl deficiency were fully rescued by ablation of maternal Gnas, but not vice versa, suggesting that XLαs, despite the phenotypic impact caused by its ablation, is limited to a modulatory role. This outcome was manifest, for example, in a molecular assay measuring signalling in brown fat, consistent with a role for direct antagonism between Gsα and XLα in this tissue. Antagonism in phenotypes affecting energy homeostasis is predicted by the conflict theory for the evolution of genomic imprinting and the evolutionary functional significance of the data is considered in light of the revealed types of interaction occurring (irrespective of their mechanisms) and considering the types of phenotype affected by these interactions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available