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1. Baxley, Sarah. The role of WNT5A in mammary gland development.

Degree: PhD, 2010, University of Alabama – Birmingham

Transforming growth factor {esc}gb {esc}s(TGF-{esc}gb{esc}s) negatively regulates mammary gland development and requires Wnt5a to exert some of these effects on mammary gland development. Wnt5a is a non-canonical signaling Wnt that is expressed in all stages of mammary gland development except lactation. Using slow release pellets containing Wnt5a, as well as Wnt5a null tissue, we previously showed that Wnt5a also acts to limit mammary development. Initial studies revealed a potential role for TGF-{esc}gb {esc}sand Wnt5a in regulating mammary gland progenitor cells, indicating they may act to regulate the stem and progenitor cell population. In order to study the role of Wnt5a on mammary stem and progenitor cell maintenance, we wanted to create a new mouse model. Here, we generated transgenic mice that overexpress Wnt5a in the mammary epithelium using the MMTV promoter (M5a mice). Lactation was impaired in two high Wnt5a expressing lines. Lactation defects could not be explained by differences in apoptosis, lineage differentiation, milk synthesis or secretion. Instead, Wnt5a overexpression led to a failure in oxytocin response and milk ejection, similar to mice with a mutation in Connexin43 (Cx43), we examined Cx43 phosphorylation and localization in M5a mice. In wild type mice, Cx43 switched from a phosphorylated to a more hypophosphorylated form after parturition. In contrast, Cx43 was maintained in the phosphorylated form after parturition in M5a mice. Similarly, mammary myoepithelial cells grown in culture and treated with Wnt5a exhibited altered Cx43 phosphorylation relative to vehicle treated control cells. We propose that Wnt5a inhibits the response to oxytocin and prevents milk ejection through regulation of Cx43 phosphorylation. Additionally, we examined the effects of Wnt5a and TGF-{esc}gb {esc}son mammary stem cell populations and found no direct, significant effects on stem cell number. Although Wnt5a and TGF-{esc}gb {esc}smay not regulate stem cell number, we hypothesize they may direct other aspects of stem or progenitor cell maintenance, such as progenitor proliferation or stem cell self-renewal. Overall, we conclude that Wnt5a and TGF-{esc}gb {esc}smay regulate the mammary progenitor cell population. Additionally, Wnt5a overexpression can alter mammary Cx43 phosphorylation at parturition, inhibiting the milk ejection response.

1 online resource (x, 85 pages) :illustrations

University of Alabama at Birmingham2010.

Cell Biology

Joint Health Sciences

UNRESTRICTED

Advisors/Committee Members: Rosa Serra, Anupam Agarwal<br>, Chenbei Chang<br>, Andra Frost<br>, Christopher Klug<br>, Jianbo Wang..

Subjects/Keywords: Breast Neoplasms<; br>; Lactation<; br>; Mammary Glands, Animal – metabolism<; br>; Mammary Neoplasms, Experimental – metabolism.<; br>; Transforming Growth Factor beta – metabolism<; br>; Wnt Proteins – metabolism.

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Baxley, S. (2010). The role of WNT5A in mammary gland development. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,1812

Chicago Manual of Style (16th Edition):

Baxley, Sarah. “The role of WNT5A in mammary gland development.” 2010. Doctoral Dissertation, University of Alabama – Birmingham. Accessed December 12, 2019. http://contentdm.mhsl.uab.edu/u?/etd,1812.

MLA Handbook (7th Edition):

Baxley, Sarah. “The role of WNT5A in mammary gland development.” 2010. Web. 12 Dec 2019.

Vancouver:

Baxley S. The role of WNT5A in mammary gland development. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2010. [cited 2019 Dec 12]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,1812.

Council of Science Editors:

Baxley S. The role of WNT5A in mammary gland development. [Doctoral Dissertation]. University of Alabama – Birmingham; 2010. Available from: http://contentdm.mhsl.uab.edu/u?/etd,1812

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