Abstract
BackgroundMorphogenesis results from the coordination of distinct cell signaling pathways controlling migration, differentiation, apoptosis, and proliferation, along stem/progenitor cell dynamics. To decipher this puzzle, we focused on epithelial-mesenchymal transition (EMT) “master genes”. EMT has emerged as a unifying concept, involving cell-cell adhesion, migration and apoptotic pathways. EMT also appears to mingle with stemness. However, very little is known on the physiological role and relevance of EMT master-genes. We addressed this question during mammary morphogenesis. Recently, a link between Slug/Snai2 and stemness has been described in mammary epithelial cells, but EMT master genes actual localization, role and targets during mammary gland morphogenesis are not known and we focused on this basic question.Methodology/Principal FindingsUsing a Slug–lacZ transgenic model and immunolocalization, we located Slug in a distinct subpopulation covering about 10–20% basal cap and duct cells, mostly cycling cells, coexpressed with basal markers P-cadherin, CK5 and CD49f. During puberty, Slug-deficient mammary epithelium exhibited a delayed development after transplantation, contained less cycling cells, and overexpressed CK8/18, ER, GATA3 and BMI1 genes, linked to luminal lineage. Other EMT master genes were overexpressed, suggesting compensation mechanisms. Gain/loss-of-function in vitro experiments confirmed Slug control of mammary epithelial cell luminal differentiation and proliferation. In addition, they showed that Slug enhances specifically clonal mammosphere emergence and growth, cell motility, and represses apoptosis. Strikingly, Slug-deprived mammary epithelial cells lost their potential to generate secondary clonal mammospheres.Conclusions/SignificanceWe conclude that Slug pathway controls the growth dynamics of a subpopulation of cycling progenitor basal cells during mammary morphogenesis. Overall, our data better define a key mechanism coordinating cell lineage dynamics and morphogenesis, and provide physiological relevance to broadening EMT pathways.
Highlights
Epithelial-mesenchymal transition (EMT) is defined by a rapid change of cell phenotype
Slug was found to be only expressed by the basal fraction: CD24 med, CD49 high, CK14 high, CK18 neg
We localized Slug in vivo in mammary glands at cellular level, using both immunolabeling and a transgenic mouse
Summary
Epithelial-mesenchymal transition (EMT) is defined by a rapid change of cell phenotype. EMT pathways appear to mingle with early differentiation pathways and stem cell maintenance or emergence [3,4]. Slug has been found in the basal-like cell fraction obtained by CD24/CD49 or CD49/CD61 based-FACS analysis of mouse mammary epithelial cells [3]. We focused on physiological roles for Slug during mammary gland morphogenesis. Adult mammary gland goes through cyclic changes in response to hormonal signaling. We tested Slug role in controlling mammary epithelial cell expansion in vitro using gain or loss of function experiments. All together, these results emphasize a role for Slug in the dynamics of stem/progenitor cells renewal and/or maintenance
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