title: Caspase 3 cleavage of Pax7 inhibits self-renewal of satellite cells.
abstract: Compensatory growth and regeneration of skeletal muscle is dependent on the resident stem cell population, satellite cells (SCs). Self-renewal and maintenance of the SC niche is coordinated by the paired-box transcription factor Pax7, and yet continued expression of this protein inhibits the myoblast differentiation program. As such, the reduction or removal of Pax7 may denote a key prerequisite for SCs to abandon self-renewal and acquire differentiation competence. Here, we identify caspase 3 cleavage inactivation of Pax7 as a crucial step for terminating the self-renewal process. Inhibition of caspase 3 results in elevated Pax7 protein and SC self-renewal, whereas caspase activation leads to Pax7 cleavage and initiation of the myogenic differentiation program. Moreover, in vivo inhibition of caspase 3 activity leads to a profound disruption in skeletal muscle regeneration with an accumulation of SCs within the niche. We have also noted that casein kinase 2 (CK2)-directed phosphorylation of Pax7 attenuates caspase-directed cleavage. Together, these results demonstrate that SC fate is dependent on opposing posttranslational modifications of the Pax7 protein.
authors.affiliation: Regenerative Medicine Program, Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8L6;
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Dick
authors.affiliation: Regenerative Medicine Program, Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6;
authors.forename: Natasha C
authors.initials: NC
authors.lastname: Chang
authors.affiliation: Regenerative Medicine Program, Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6;
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Dumont
authors.affiliation: Regenerative Medicine Program, Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6;
authors.forename: Ryan A V
authors.initials: RA
authors.lastname: Bell
authors.affiliation: Regenerative Medicine Program, Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8L6;
authors.forename: Charis
authors.initials: C
authors.lastname: Putinski
authors.affiliation: Regenerative Medicine Program, Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6;
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kawabe
authors.affiliation: Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada N6A 5C1;
authors.forename: David W
authors.initials: DW
authors.lastname: Litchfield
authors.affiliation: Regenerative Medicine Program, Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8L6; Department of Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8L6.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rudnicki
authors.affiliation: Regenerative Medicine Program, Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8L6; Department of Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8L6 lmegeney@ohri.ca.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Megeney
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D047388:Casein Kinases / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism*; D051763:PAX7 Transcription Factor / Q000378:metabolism*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000378:metabolism; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology*; D017386:Sequence Homology, Amino Acid; D013234:Stem Cells / Q000166:cytology
chemical_list: D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D011994:Recombinant Proteins; D047388:Casein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Pax7; casein kinase 2; caspase; satellite cells; self-renewal