The E3 ubiquitin ligase Nedd4L preserves skeletal muscle stem cell quiescence by inhibiting their activation
Darren M. Blackburn,
Korin Sahinyan,
Aldo Hernández-Corchado,
Felicia Lazure,
Vincent Richard,
Laura Raco,
Gabrielle Perron,
René P. Zahedi,
Christoph H. Borchers,
Christoph Lepper,
Hiroshi Kawabe,
Arezu Jahani-Asl,
Hamed S. Najafabadi,
Vahab D. Soleimani
Affiliations
Darren M. Blackburn
Department of Human Genetics, McGill University, 3640 rue University, Montréal, QC H3A 0C7, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte- Sainte-Catherine, Montréal, QC H3T 1E2, Canada
Korin Sahinyan
Department of Human Genetics, McGill University, 3640 rue University, Montréal, QC H3A 0C7, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte- Sainte-Catherine, Montréal, QC H3T 1E2, Canada
Aldo Hernández-Corchado
Department of Human Genetics, McGill University, 3640 rue University, Montréal, QC H3A 0C7, Canada
Felicia Lazure
Department of Human Genetics, McGill University, 3640 rue University, Montréal, QC H3A 0C7, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte- Sainte-Catherine, Montréal, QC H3T 1E2, Canada
Vincent Richard
Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada
Laura Raco
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte- Sainte-Catherine, Montréal, QC H3T 1E2, Canada
Gabrielle Perron
Department of Human Genetics, McGill University, 3640 rue University, Montréal, QC H3A 0C7, Canada
René P. Zahedi
Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada; Manitoba Centre for Proteomics and Systems Biology, Winnipeg, MB R3E 3P4, Canada; Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3E 3P4, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Christoph H. Borchers
Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC H3T 1E2, Canada; Division of Experimental Medicine, McGill University, Montréal, QC H4A 3J1, Canada; Department of Pathology, McGill University, Montréal, QC H3A 2B4, Canada
Christoph Lepper
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA
Hiroshi Kawabe
Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine 37075 Göttingen, Germany
Arezu Jahani-Asl
Department of Cellular and Molecular Medicine and University of Ottawa Brain and Mind Research Institute, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada
Hamed S. Najafabadi
Department of Human Genetics, McGill University, 3640 rue University, Montréal, QC H3A 0C7, Canada
Vahab D. Soleimani
Department of Human Genetics, McGill University, 3640 rue University, Montréal, QC H3A 0C7, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte- Sainte-Catherine, Montréal, QC H3T 1E2, Canada; Department of Biochemistry, Microbiology & Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada; Corresponding author
Summary: Adult stem cells play a critical role in tissue repair and maintenance. In tissues with slow turnover, including skeletal muscle, these cells are maintained in a mitotically quiescent state yet remain poised to re-enter the cell cycle to replenish themselves and regenerate the tissue. Using a panomics approach we show that the PAX7/NEDD4L axis acts against muscle stem cell activation in homeostatic skeletal muscle. Our findings suggest that PAX7 transcriptionally activates the E3 ubiquitin ligase Nedd4L and that the conditional genetic deletion of Nedd4L impairs muscle stem cell quiescence, with an upregulation of cell cycle and myogenic differentiation genes. Loss of Nedd4L in muscle stem cells results in the expression of doublecortin (DCX), which is exclusively expressed during their in vivo activation. Together, these data establish that the ubiquitin proteasome system, mediated by Nedd4L, is a key contributor to the muscle stem cell quiescent state in adult mice.
