Caspase 3 cleavage of Pax7 inhibits self-renewal of satellite cells

Sarah A. Dick, Natasha C. Chang, Nicolas A. Dumont, Ryan A V Bell, Charis Putinski, Yoichi Kawabe, David W. Litchfield, Michael A. Rudnicki, Lynn A. Megeney, Eric N. Olson

Research output: Contribution to journalArticle

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E5246-E5252
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number38
DOIs
StatePublished - Sep 22 2015

Keywords

  • Casein kinase 2
  • Caspase
  • Pax7
  • Satellite cells
  • Self-renewal

ASJC Scopus subject areas

  • General

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    Dick, S. A., Chang, N. C., Dumont, N. A., Bell, R. A. V., Putinski, C., Kawabe, Y., Litchfield, D. W., Rudnicki, M. A., Megeney, L. A., & Olson, E. N. (2015). Caspase 3 cleavage of Pax7 inhibits self-renewal of satellite cells. Proceedings of the National Academy of Sciences of the United States of America, 112(38), E5246-E5252. https://doi.org/10.1073/pnas.1512869112