Stölzle, Tina. Physiological roles of the oncoprotein c-Myc in mouse mammary gland development. 2009, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_8950
To address this open question and uncover the roles of c-Myc during mouse mammary gland development, we used a mammary gland specific conditional knockout approach, as the full body knockout of c-Myc is embryonic lethal. For this, we crossed c-mycfl/fl mice to mice heterozygous for the WAPiCre transgene (Cre recombinase under the control of the Whey acidic protein promoter). This resulted in c-Myc loss exclusively in the milk-producing, luminal alveolar epithelial cells starting in mid-pregnancy. Three major phenotypes were identified in the glands of mutant mice. First, we observed that pups nursed by c-Myc mutant mothers grew slower compared to pups nursed by wild type mothers. While milk composition was comparable between wild type and mutant animals, we found that milk production was reduced in c-Myc mutant glands. Electron microscopy revealed that there were less secretory vesicles budding from the endoplasmic reticulum in lactating mutant cells, suggesting a decreased protein synthesis. By performing polysome fractionation experiments we showed that translational efficiency was generally decreased in mutant glands. In addition, we found that levels of ribosomal proteins and rRNA were lower in mutant glands. Interestingly, analyzing mRNA distribution along the polysome gradient demonstrated that mRNAs whose protein products are involved in milk synthesis were specifically affected while mRNAs of house keeping genes were generally unchanged. Our second major finding was that in a second round of pregnancy, c-Myc-deficient cells displayed a slower proliferation early during pregnancy. The delayed proliferative response led to delayed but not blocked alveologenesis. Finally, the third major observation in c-Myc-deficient glands is related to progenitor cells. In mammary transplantation assays, epithelium from mutant glands showed a reduced ability to repopulate the glands of female recipients compared to epithelium from wild type glands, suggesting a role for c-Myc during this process.
To summarize, we show here for the first time that c-Myc plays multiple roles in the mouse mammary gland. Conditional loss of c-Myc caused delayed proliferation and differentiation during pregnancy. During lactation, milk production and translation were decreased in mutant glands. Finally, results from transplantation studies suggest a role for c-Myc in progenitor cell proliferation and/or survival.
|Committee Members:||Trumpp, Andreas and Matthias, Patrick D.|
|Faculties and Departments:||09 Associated Institutions > Friedrich Miescher Institut FMI|
|Bibsysno:||Link to catalogue|
|Number of Pages:||127 S.|
|Last Modified:||30 Jun 2016 10:41|
|Deposited On:||07 May 2010 06:53|
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