By using different strategies, several recent studies all demonstrate that the BMP/Smad pathway plays important roles in postnatal muscle satellite cells (MuSCs): it regulates both the establishment of the adult muscle satellite cell pool and injury-induced muscle regeneration. It remains unclear whether this pathway also regulates the self-renewal of MuSCs. Here, by inducible deletion of Smad4, the indispensable co-Smad of the BMP pathway, we not only confirmed previous findings, but also revealed that the BMP/Smad pathway critically regulates the self-renewal ability of adult MuSCs. Mechanistically, we found that the Id family members and Cdkn1c (p57) were crucial downstream targets of Smad4 in suppressing precocious differentiation. Moreover, both myomaker and myomixer, two genes who...[ Read more ]

By using different strategies, several recent studies all demonstrate that the BMP/Smad pathway plays important roles in postnatal muscle satellite cells (MuSCs): it regulates both the establishment of the adult muscle satellite cell pool and injury-induced muscle regeneration. It remains unclear whether this pathway also regulates the self-renewal of MuSCs. Here, by inducible deletion of Smad4, the indispensable co-Smad of the BMP pathway, we not only confirmed previous findings, but also revealed that the BMP/Smad pathway critically regulates the self-renewal ability of adult MuSCs. Mechanistically, we found that the Id family members and Cdkn1c (p57) were crucial downstream targets of Smad4 in suppressing precocious differentiation. Moreover, both myomaker and myomixer, two genes whose products promote myoblast fusion, were also found to be transcription targets of Smad4. Thus, the BMP/Smad pathway regulates various phases of postnatal MuSCs (i.e., establishment of the adult MuSC pool, injury-induced muscle regeneration, and self-renewal) by a common mode: it potently prevents precocious differentiation of MuSCs to ensure they have a critical time window to expand.