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Cell Rep. 2017 Mar 7;18(10):2320-2330. doi: 10.1016/j.celrep.2017.02.036.

R-spondin1 Controls Muscle Cell Fusion through Dual Regulation of Antagonistic Wnt Signaling Pathways.

Author information

1
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, 75013 Paris, France.
2
Département de pharmacologie et physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, J1H5N4 QC, Canada.
3
Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, K1H8L6 ON, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, K1H 8M5 ON, Canada.
4
School of Biological Sciences, University of Reading, RG6 6UB Reading, UK.
5
School of Biological Sciences, University of Reading, RG6 6UB Reading, UK; Freiburg Institute for Advanced Studies, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg im Breisgau, Germany.
6
Université Côte d'Azur, INSERM, CNRS, iBV, 06108 Nice, France.
7
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, 75013 Paris, France. Electronic address: fabienlegrand@gmail.com.

Abstract

Wnt-mediated signals are involved in many important steps in mammalian regeneration. In multiple cell types, the R-spondin (Rspo) family of secreted proteins potently activates the canonical Wnt/β-catenin pathway. Here, we identify Rspo1 as a mediator of skeletal muscle tissue repair. First, we show that deletion of Rspo1 results in global alteration of muscle regeneration kinetics following acute injury. We find that muscle progenitor cells lacking Rspo1 show delayed differentiation due to reduced activation of Wnt/β-catenin target genes. Furthermore, muscle cells lacking Rspo1 have a fusion phenotype leading to larger myotubes containing supernumerary nuclei both in vitro and in vivo. The increase in muscle fusion was dependent on downregulation of Wnt/β-catenin and upregulation of non-canonical Wnt7a/Fzd7/Rac1 signaling. We conclude that reciprocal control of antagonistic Wnt signaling pathways by Rspo1 in muscle stem cell progeny is a key step ensuring normal tissue architecture restoration following acute damage.

KEYWORDS:

R-spondin; canonical Wnt signaling; muscle satellite cell; non-canonical Wnt signaling; regeneration; skeletal muscle

PMID:
28273449
PMCID:
PMC5357729
DOI:
10.1016/j.celrep.2017.02.036
[Indexed for MEDLINE]
Free PMC Article

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