Project Summary There is currently significant interest in the potential for skeletal muscle stem cells, known as satellite cells, to be used in regenerative tissue therapy. The molecular understanding of skeletal muscle stem cell maintenance, fate determination and differentiation is crucial for translating research to the treatment of degenerative muscle diseases where there are few effective treatment options. This proposal investigates how the program of muscle stem cell maintenance, renewal and regeneration are orchestrated by selective, accelerated mRNA decay directed by the protein AUF1. This is a highly important but largely understudied area of gene regulation that plays a major role in programming and controlling adult tissue stem cell fate and tissue regeneration. We build on our previous studies and propose to identify the factors that regulate AUF1 expression in the satellite cell because AUF1 orchestrates the muscle regeneration program of the satellite cell, identify the satellite cell mRNAs selectively targeted for rapid degradation by AUF1 because this appears to stage the different developmental events of muscle regeneration, and how AUF1 orchestrates the progression of reprogramming by interacting with key regulatory proteins because this controls fate determination of satellite cells from activation to muscle regeneration.