Slug controls stem/progenitor cell growth dynamics during mammary gland morphogenesis

Area of Science:

• Developmental Biology
• Cell Biology
• Stem Cell Biology

Background:

• Mammary gland morphogenesis involves complex cell signaling pathways, including epithelial-mesenchymal transition (EMT).
• EMT master genes' physiological roles in mammary development and stemness remain largely unknown.
• Slug (Snai2) has been linked to stemness in mammary cells, but its specific function in morphogenesis is unclear.

Purpose of the Study:

• To investigate the localization, role, and targets of EMT master genes during mammary gland morphogenesis.
• To elucidate the function of Slug in regulating mammary epithelial cell dynamics and stemness.

Main Methods:

• Utilized a Slug-lacZ transgenic model for localization studies.
• Performed immunolocalization and analyzed gene expression in Slug-deficient mammary epithelium.
• Conducted in vitro gain/loss-of-function experiments on mammary epithelial cells.
• Assessed effects on cell proliferation, differentiation, apoptosis, and mammosphere formation.

Main Results:

• Slug is localized in a subpopulation of basal/duct cells, primarily cycling cells, coexpressed with basal markers.
• Slug-deficient mammary epithelium shows delayed development, reduced cycling cells, and altered luminal lineage gene expression.
• Slug promotes mammary epithelial cell proliferation, luminal differentiation, cell motility, and mammosphere formation while repressing apoptosis.
• Slug deprivation significantly impairs the generation of secondary mammospheres, indicating a loss of stem cell potential.

Conclusions:

• Slug pathway is critical for regulating the growth dynamics of cycling progenitor basal cells during mammary morphogenesis.
• Slug controls mammary epithelial cell proliferation, differentiation, and stemness, coordinating cell lineage dynamics.
• These findings provide physiological relevance to EMT pathways and define a key mechanism in mammary gland development.