PROJECT SUMMARY Coordination of cell migration, proliferation and cell fate determination is critical for stem cell function and tissue repair. We have identified that P16Ink4a, the classic pro-senescence and aging regulator, participates in the regulation of healthy adult muscle stem cells. We find a role for P16Ink4a in cell migration and cell fate decisions via the cytoskeleton and contractile machinery. This has not been reported previously. The long-term goal is to understand how P16Ink4a is induced and regulates cytoskeletal function of healthy progenitor cells in non-aged tissues. The first aim will combine temporal regulated and cell specific genetic strategies to determine the role of P16Ink4a in healthy adult muscle stem cells. The second aim will dissect the functional and molecular mechanism that regulates cell mechanics, migration and cell fate via P16Ink4a. The third aim will examine the role of P16Ink4a in cell autonomous regulation of its own microenvironment. Understanding the role of P16Ink4a in progenitor cell function will lead to important insights for aging, senescence, cancer and muscle degenerative diseases.