An FAK-YAP-mTOR Signaling Axis Regulates Stem Cell-Based Tissue Renewal in Mice

Tissue homeostasis requires the production of newly differentiated cells from resident adult stem cells. Central to this process is the expansion of undifferentiated intermediates known as transit-amplifying (TA) cells, but how stem cells are triggered to enter this proliferative TA state remains an important open question. Using the continuously growing mouse incisor as a model of stem cell-based tissue renewal, we found that the transcriptional cofactors YAP and TAZ are required both to maintain TA cell proliferation and to inhibit differentiation. Specifically, we identified a pathway involving activation of integrin α3 in TA cells that signals through an LATS-independent FAK/CDC42/PP1A cascade to control YAP-S397 phosphorylation and nuclear localization. This leads to Rheb expression and potentiates mTOR signaling to drive the proliferation of TA cells. These findings thus reveal a YAP/TAZ signaling mechanism that coordinates stem cell expansion and differentiation during organ renewal. [Display omitted] •The YAP/TAZ transcriptional cofactors are required for incisor maintenance•YAP/TAZ prevent premature differentiation of transit-amplifying (TA) cells•YAP/TAZ activate mTOR signaling to promote TA cell proliferation•Integrin α3 and FAK regulate YAP nuclear localization via CDC42 and PP1A Klein and colleagues show, using the mouse incisor as a model, that the transcriptional cofactors YAP and TAZ, components of the Hippo pathway, regulate stem cell-based tissue renewal by controlling the proliferation and differentiation of transit-amplifying cells in response to integrin/FAK signaling.