Résumé :
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During development, founder stem cells proliferate, and cell cycle exit is generally restricted to differentiating cells. In contrast, adult stem cells, can assume different cellular states, either quiescence or proliferating. After embryonic development is complete, a pool of juvenile and adult satellite cells is allocated for postnatal skeletal muscle growth and regeneration. Our studies have shown that the transition from proliferating to quiescent cells initiates from about 2 weeks after birth in the mouse until the majority of satellite cells exit the cell cycle in the young adult (4-5 weeks postnatally). One candidate for controlling satellite cell quiescence is the highly conserved Notch signaling pathway, whose activity has been shown to be instrumental for the regulation of cell fates and proliferation in a variety of tissues. Notch has been shown to have anti-myogenic activity and disruption of this pathway leads to premature muscle differentiation at the expense of muscle stem/progenitors. In spite of the pleiotropic effects of Notch, a role of this critical pathway in quiescent adult stem cells was reported only for neural stem cells in the adult brain. Using a transgenic Tg:Pax7-nGFP mouse to isolate muscle stem/progenitor cells, we performed a temporal and ontological assessment of effectors of Notch signalling. We uncover a dynamic expression of specific Notch pathway components as cells differentiate, and during development, notably with highest activity restricted to less committed cells as well as quiescent satellite cells. We used genetic tools to block Notch activity by conditionally abrogating Rbpj function, the transcription factor which mediates Notch signalling, in satellite cells during homeostasis. We demonstrate that Notch activity is crucial for maintaining the quiescent muscle stem cell state. In the absence of Notch signalling, satellite cells spontaneously differentiate and contribute to myofibres, thereby resulting in a severe depletion of the stem cell pool. This study establishes Notch signaling as the first regulator of cellular quiescence in adult muscle stem cells.
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