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F-actin dynamics regulates mammalian organ growth and cell fate maintenance

ABSTRACT: Cell function depends on the mechanical properties of the microenvironment. Cells probe these features by applying and transmitting forces to their surroundings, via their actomyosin cytoskeleton and adhesion complexes, and then transducing them into biochemical signals. Among these, the transcriptional coactivators YAP/TAZ recently emerged as key factors mediating some biological responses to actomyosin contractility in vitro. However, whether mechanical cues regulate YAP/TAZ activity in vivo, and whether this is relevant for adult tissue homeostasis, remains poorly understood. Here we show that the F-actin capping protein CAPZ is a critical regulator of actomyosin contractility, as its inactivation alters stress fiber and focal adhesion dynamics, leading to enhanced myosin activity and increased cellular traction forces. In vitro, this rescues YAP from inhibition by a small geometry; in vivo, inactivation of Capzb in the mouse liver induces YAP activation and hepatocyte proliferation, leading to striking organ overgrowth. Moreover, Capzb is essential for the maintenance of the differentiated hepatocyte state, and for the metabolic zonation of hepatocytes. In keeping with changes in tissue mechanics and activation of YAP, inhibition of ROCK or deletion of Yap1 reverse the phenotypes emerging in Capzb-null livers. These results indicate a previously unrecognized role for CAPZ in tuning the sensitivity of cells and tissues to mechanical signals, and a physiological function for F-actin dynamics in regulating organ growth and tissue homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE116993 | GEO | 2019/03/19

REPOSITORIES: GEO

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