Stabilization of Epithelial β-Catenin Compromises Mammary Cell Fate Acquisition and Branching Morphogenesis

The Wnt/β-catenin pathway plays a critical role in cell fate specification, morphogenesis, and stem cell activation across diverse tissues, including the skin. In mammals, the embryonic surface epithelium gives rise to the epidermis as well as the associated appendages including hair follicles and mammary glands, both of which depend on epithelial Wnt/β-catenin activity for initiation of their development. Later on, Wnts are thought to enhance mammary gland growth and branching, whereas in hair follicles, they are essential for hair shaft formation. In this study, we report a strong downregulation of epithelial Wnt/β-catenin activity as the mammary bud progresses to branching. We show that forced activation of epithelial β-catenin severely compromises embryonic mammary gland branching. However, the phenotype of conditional Lef1-deficient embryos implies that a low level of Wnt/β-catenin activity is necessary for mammary cell survival. Transcriptomic profiling suggests that sustained high β-catenin activity leads to maintenance of mammary bud gene signature at the expense of outgrowth/branching gene signature. In addition, it leads to upregulation of epidermal differentiation genes. Strikingly, we find a partial switch to hair follicle fate early on upon stabilization of β-catenin, suggesting that the level of epithelial Wnt/β-catenin signaling activity may contribute to the choice between skin appendage identities.