Résumé :
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Muscle cell formation is a coordinated process of tissue-specific gene expression, proliferation and differentiation. In order to safeguard the developing progenitor cells against a prolonged proliferation or a premature differentiation, cell cycle exit has to be tightly regulated. In the myogenic lineage, irreversible cell cycle exit is controlled by the Cyclin Dependent Kinase Inhibitors (CDKIs) p21 and p57. Mice lacking these two genes harbor severe muscle defects. Using MyoD-/- and p21-/- ; p57+/-m mutant embryos, we found that Myf5 is sufficient to trigger p57 expression, indicating that cell cycle exit is associated with cell determination. Moreover we show that during development, growth arrest is uncoupled from cell differentiation. Next, using MyoD-/- ; Myf5nLacZ/nLacZ mutant, in which myogenesis is abrogated, we found that determined myoblasts control Pax3+ cells proliferation by preventing them from activating p57 and exiting cell cycle. We show that this control is mediated by the Notch pathway through the Notch-regulated genes Hes1, Hey1 and HeyL, which are down regulated in MyoD-/- ; Myf5nLacZ/nLacZ mutant embryos. Finally, we have identified a p57 specific Muscle Regulatory Element and found that, in vivo, bHLH transcription activator MyoD and the transcriptional repressor Hes1 are bound to this element. Thus, we have identified a molecular mechanism whereby the direct interaction between early post-mitotic myoblasts and progenitor cells allows the activation of Notch target gene Hes1 in Pax3+ cells, which in turn suppress p57 expression, keeping the progenitor cell cycling. This mechanism ensures the regulated equilibrium between building muscles and maintaining the pool of undifferentiated progenitors cells.
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