YAP/TAZ-controlled ERK dynamics coordinate progenitor expansion and differentiation commitment

Progenitor cells need to divide to increase the overall cell count, but they must eventually stop dividing to differentiate into specialized cells. How different signaling pathways regulate the length of the proliferation window is not well understood. By studying adipogenesis through live single-cell imaging and tracking cell-cycle and ERK-activity, researchers have discovered that YAP and TAZ proteins work together to coordinate progenitor expansion with the decision to differentiate.

YAP/TAZ proteins keep cells in a state of fluctuating high ERK activity, which encourages cell division while simultaneously preventing the transcription factor PPARG from pushing cells past the point of irreversible commitment to differentiation. This block in differentiation is not solely due to increased cell division: inhibiting CDK4/6 or AKT leads to reduced cell division without triggering differentiation, while inhibiting MEK-ERK leads to differentiation even when YAP/TAZ activity remains high.

As YAP/TAZ activity decreases, ERK activity becomes more stable, activating PPARG. The findings suggest a self-limiting process where YAP/TAZ-driven expansion of progenitor cells gradually increases cell density and promotes contact-dependent signaling through the Hippo pathway, reducing YAP/TAZ activity and ending the proliferative phase.

As YAP/TAZ activity wanes, progenitor expansion expands the progenitor population while maintaining the ability to differentiate, whereas continuous YAP/TAZ activity suppresses differentiation. In conclusion, these findings reveal that YAP/TAZ-controlled ERK dynamics serve as a critical link between the expansion of progenitor cells and the commitment to differentiation, and suggest that the duration of the proliferative window may be regulated by the density-dependent feedback from the Hippo pathway to control the number of differentiated cells.