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    • br Introduction Stem cells are essential for tissue

    2018-10-20


    Introduction Stem cells are essential for tissue formation, maintenance, and repair by achieving a timely balance between error-free replicative expansion and differentiation. This balance is frequently jeopardized in cancer and aging, leading to tissue pathology and functional decline (Blanpain et al., 2011; Liu and Rando, 2011; Ricke and van Deursen, 2013). To ensure accurate segregation of chromosomes during mitosis, the spindle assembly checkpoint (SAC) prevents ctap Supplier onset until each chromosome has attached properly to mitotic spindle microtubules via its kinetochore (Foley and Kapoor, 2013; Lara-Gonzalez et al., 2012; Musacchio and Salmon, 2007). Therefore, an active SAC will delay mitosis until all chromosomes have been properly attached and aligned. Many molecular players participate in a spatiotemporally concerted manner to actuate the SAC. These include MAD2 (mitotic arrest deficient 2), MPS1 (monopolar spindle 1), BUB1 (budding uninhibited by benomyl 1), and BUBR1 (Foley and Kapoor, 2013; Lara-Gonzalez et al., 2012; Musacchio and Salmon, 2007; Suijkerbuijk et al., 2012). In the presence of improperly attached kinetochores, the SAC arrests cells in mitosis by inhibiting the ability of CDC20 to activate APC/C-mediated polyubiquitination and subsequent proteasomal degradation of securin and cyclin B1 (Hwang et al., 1998; Kim et al., 1998). SAC disruption in different cellular contexts reveals distinct outcomes. Data from immortalized cell lines and single-cell organisms demonstrate that the consequences of SAC failure include premature onset of anaphase, mitotic slippage, chromosome missegregation, and promotion of aneuploidy (Jelluma et al., 2008; Kops et al., 2004). In vivo studies in vertebrates and invertebrates show the consequence of SAC failure to be context dependent. During development, defective SAC activity can be tolerated early during embryogenesis but leads to an eventual loss of viability (Dobles et al., 2000; Fischer et al., 2004). Similarly, a reduction in MAD2 and BUBR1 leads to a SAC defect that can be tolerated but accelerates tumor production (Dai et al., 2004; Michel et al., 2001). In contrast, the SAC is essential during development and adult tissue regeneration in zebrafish (Poss et al., 2002a, 2002b, 2004). Studies on the role of the SAC in stem cells are more limited. Using either germline mutants or developmentally induced Cre drivers to delete SAC genes, both hematopoietic stem cells and epidermal stem cells and their respective committed progeny display differential sensitivity to SAC disruption (Foijer et al., 2013; Ito et al., 2007). Sensitivity to SAC dysfunction in epidermal stem cells was associated with increased aneuploidy and apoptosis (Foijer et al., 2013). To date, the role of the SAC exclusively in adult mammalian stem cells has not been addressed. Pax7-expressing satellite cells (SCs) possess the function of stem cells and are critical for postnatal growth and repair of adult skeletal muscle (Lepper et al., 2009; Murphy et al., 2011; Sambasivan et al., 2011; Seale et al., 2000). Using inducible Pax7-specific SAC perturbation models, we show that the SAC is essential for normal mammalian SC function, during both early postnatal growth and adult tissue regeneration. Deregulation of the SAC in SC progeny leads to a rapid G1 arrest and missegregation of chromosomes. p21CIP1 is critical for the cellular arrest, and its reduction in SAC-defective progenitors permits the expansion of SCs with faulty genomes. Furthermore, we show that SAC activity and the level of aneuploidy are not altered in cycling satellite cells as a function of physiological aging.
    Results
    Discussion The long-lived nature of stem cells imperils them to accumulate genomic damage or errors, which may lead to tissue degeneration or oncogenesis, depending on the cellular response to the insult. The SAC is an essential component of mitosis to ensure fidelity of chromosome segregation during replication. Using targeted approaches to target SAC function specifically in skeletal muscle stem cells, we show that the SAC is essential for muscle stem cell function both during early postnatal growth and adult tissue regeneration. Muscle stem cells lacking a functional SAC arrest in G1 phase of the cell cycle with missegregated chromosomes (aneuploidy) and are incapable of differentiation. The cell-cycle inhibitor p21CIP1 acts as a gatekeeper to protect muscle stem cells from propagating abnormal genomes at the expense of tissue repair.