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An Investigation into the Role of the MARRS Receptor in Murine Mammary Gland Growth and Development

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Title: An Investigation into the Role of the MARRS Receptor in Murine Mammary Gland Growth and Development
Author: Wilkin, Allison
Department: Department of Human Health and Nutritional Sciences
Program: Human Health and Nutritional Sciences
Advisor: Meckling, Kelly
Abstract: Vitamin D has been implicated in mammary gland development, however nothing is known about the role of the second 1,25-dihydroxyvitamin D3 (1,25D3) receptor MARRS and its effects on post-natal mammary gland development or interaction with 1,25D3 in this tissue. Therefore, the objectives of this thesis were to investigate these unknowns in a tissue-specific knockout mouse model. In study 1, MARRS was knocked out in murine mammary gland epithelial cells of 4-week old mice (n=30). Several markers of mammary gland (MG) growth were measured, including number of terminal end buds (TEB), ductal coverage of the fat pad, and ductal extension. It was found that the knockout animals had decreased numbers of TEBs (p=0.019), and decreased ductal extension (p=0.018). Study 2 aimed to expand the investigation to MARRS’s actions with varying vitamin D3 dietary dose. Abdominal MGs were collected from 6-week old MARRS knockout female mice (n=94) on diets of 10,000 IU/kg (replete), 1,000 IU/kg (sufficient) or 0 IU/kg (deficient) of D3. There was a significant interaction between genotype and diet regarding TEBs (p=0.001) and ductal coverage (p=0.03). Knockout mice on the sufficient diet had significantly fewer TEBs (p=0.001) compared to wildtypes on the same diet, but the opposite effect was seen in mice on the replete diet. The increased growth in knockout mice on replete diets was unexpected; therefore in Study 3, a novel double knockout mouse lacking both MARRS and VDR was created to study the actions of both pathways simultaneously. There was a significant overall interaction between genotype groups (p=0.004) regarding mean ductal coverage, yet number of TEBs remained similar across all genotypes. Overall, this thesis demonstrates that MARRS does indeed play a role in mammary gland development providing a growth-positive effect, and that effect can be altered depending on the amount of vitamin D3 available in the diet. Although neither MARRS nor VDR are essential for mammary gland growth, their signalling pathways and gene-diet interactions provide valuable information regarding dietary intakes during puberty and influences on tissue growth. These results now merit further studies in human populations to investigate dietary trends and long-term consequences in human adolescents.
Date: 2019-08
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