title: Slug controls stem/progenitor cell growth dynamics during mammary gland morphogenesis.
abstract: BACKGROUND
  Morphogenesis 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.
  
  
  RESULTS
  Using 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
  We 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.
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, Institut National de la Santé et de la Recherche Médicale U896, Université Montpellier, Centre Régional de Lutte contre le Cancer Val d'Aurelle-Paul Lamarque, Montpellier, France.
authors.forename: Mayssa
authors.initials: M
authors.lastname: Nassour
authors.forename: Ysia
authors.initials: Y
authors.lastname: Idoux-Gillet
authors.forename: Abdelkader
authors.initials: A
authors.lastname: Selmi
authors.forename: Christophe
authors.initials: C
authors.lastname: Côme
authors.forename: Maria-Luisa M
authors.initials: ML
authors.lastname: Faraldo
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Deugnier
authors.forename: Pierre
authors.initials: P
authors.lastname: Savagner
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D008321:Mammary Glands, Animal / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors