PT - JOURNAL ARTICLE AU - Floriane Lacour AU - Elsa Vezin AU - Florian Bentzinger AU - Marie-Claude Sincennes AU - Robert D. Mitchell AU - Ketan Patel AU - Michael A. Rudnicki AU - Marie-Christine Chaboissier AU - Anne-Amandine Chassot AU - Fabien Le Grand TI - R-spondin1 regulates muscle progenitor cell fusion through control of antagonist Wnt signaling pathways AID - 10.1101/063669 DP - 2016 Jan 01 TA - bioRxiv PG - 063669 4099 - http://biorxiv.org/content/early/2016/07/13/063669.short 4100 - http://biorxiv.org/content/early/2016/07/13/063669.full AB - Tissue regeneration requires the selective activation and repression of specific signaling pathways in stem cells. As such, the Wnt signaling pathways have been shown to control stem cell fate. In many cell types, the R-Spondin (Rspo) family of secreted proteins acts as potent activators of the canonical Wnt/β-catenin pathway. Here, we identify Rspo1 as a mediator of skeletal muscle tissue repair. Firstly we show that Rspo1-null muscles do not display any abnormalities at the basal level. However deletion of Rspo1 results in global alteration of muscle regeneration kinetics following acute injury. We found that muscle stem cells lacking Rspo1 show delayed differentiation. Transcriptome analysis further demonstrated that Rspo1 is required for the activation of Wnt/β-catenin target genes in muscle cells. Furthermore, muscle cells lacking Rspo1 fuse with a higher frequency than normal cells, leading to larger myotubes containing more nuclei both in vitro and in vivo. We found the increase in muscle fusion was dependent on up-regulation of non-canonical Wnt7a/Fzd7/Rac1 signaling. We conclude that antagonistic control of canonical and non-canonical Wnt signaling pathways by Rspo1 in muscle stem cell progeny is important for restitution of normal muscle architecture during skeletal muscle regeneration.