The role of beta-catenin activation in the hair follicle: A non-cell autonomous mechanism of stem cell-dependent tissue growth

While Wnt/beta-catenin signaling is critically implicated in processes as diverse as tissue regeneration and cancer, it remains unclear how beta-catenin regulates stem cell behaviors to coordinate organized growth. Using time lapse imaging of live mice, we show that oriented cell divisions and dynamic movements drive tissue regeneration in the hair follicle. Genetic activation of beta-catenin specifically within hair follicle stem cells and their progeny cells generated new, aberrant axes of hair growth through a similar mechanism of oriented cell divisions and coordinated cellular displacement. Additionally, beta-catenin activation was sufficient to induce growth within the stem cell pool, independent of mesenchymal niche signals previously shown to be required for normal hair follicle regeneration. The aberrant growths were comprised both of mutant cells with activated beta-catenin and their neighboring wild-type cells. Remarkably, wild-type cells were co-opted non-cell autonomously into new hair growths by the beta-catenin mutant cells, which activate Wnt signaling within the wild-type cells via Wnt ligands. Collectively, the work presented in this thesis demonstrates a novel mechanism by which Wnt/beta-catenin signaling controls stem cell-dependent tissue growth non--cell autonomously, and carries broader implications toward understanding mechanisms of tumor growth and tissue regeneration across tissue types.