title: The Spindle Assembly Checkpoint Safeguards Genomic Integrity of Skeletal Muscle Satellite Cells.
abstract: To ensure accurate genomic segregation, cells evolved the spindle assembly checkpoint (SAC), whose role in adult stem cells remains unknown. Inducible perturbation of a SAC kinase, Mps1, and its downstream effector, Mad2, in skeletal muscle stem cells shows the SAC to be critical for normal muscle growth, repair, and self-renewal of the stem cell pool. SAC-deficient muscle stem cells arrest in G1 phase of the cell cycle with elevated aneuploidy, resisting differentiation even under inductive conditions. p21(CIP1) is responsible for these SAC-deficient phenotypes. Despite aneuploidy's correlation with aging, we find that aged proliferating muscle stem cells display robust SAC activity without elevated aneuploidy. Thus, muscle stem cells have a two-step mechanism to safeguard their genomic integrity. The SAC prevents chromosome missegregation and, if it fails, p21(CIP1)-dependent G1 arrest limits cellular propagation and tissue integration. These mechanisms ensure that muscle stem cells with compromised genomes do not contribute to tissue homeostasis.
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02114, USA.
authors.forename: Swapna
authors.initials: S
authors.lastname: Kollu
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02114, USA.
authors.forename: Rana
authors.initials: R
authors.lastname: Abou-Khalil
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02114, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Shen
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: andrew.brack@ucsf.edu.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Brack
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints; D017404:In Situ Hybridization, Fluorescence; D018386:Kinetochores / Q000737:chemistry / Q000378:metabolism; D064246:Mad2 Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects; D018482:Muscle, Skeletal / Q000502:physiology; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015739:Nocodazole / Q000494:pharmacology; D010641:Phenotype; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; C441620:Ttk protein, mouse; D017346:Protein Serine-Threonine Kinases; D015739:Nocodazole