Developmental Stage and Time Dictate the Fate of Wnt/β-Catenin-Responsive Stem Cells in the Mammary Gland

SummaryThe mammary epithelium undergoes extensive growth and remodeling during pregnancy, suggesting a role for stem cells. Yet their origin, identity, and behavior in the intact tissue remain unknown. Using an Axin2CreERT2 allele, we labeled and traced Wnt/β-catenin-responsive cells throughout mammary gland development. This reveals a switch in Wnt/β-catenin signaling around birth and shows that, depending on the developmental stage, Axin2+ cells contribute differently to basal and luminal epithelial cell lineages of the mammary epithelium. Moreover, an important difference exists between the developmental potential tested in transplantation assays and that displayed by the same cell population in situ. Finally, Axin2+ cells in the adult build alveolar structures during multiple pregnancies, demonstrating the existence of a Wnt/β-catenin-responsive adult stem cell. Our study uncovers dynamic changes in Wnt/β-catenin signaling in the mammary epithelium and offers insights into the developmental fate of mammary gland stem and progenitor cells.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (479 K)Download as PowerPoint slideHighlights► Axin2CreERT2 allows lineage tracing of Wnt/β-catenin-responsive mammary stem cells ► A switch in Wnt-signaling around birth yields committed, Axin2+ basal stem cells ► Axin2+ stem cells in the adult virgin generate basal and luminal alveolar cells ► Transplantation unlocks a regenerative potential not used in normal development