SMAD transcription factors are key mediators of transforming growth factor beta (TGFβ) signalling. During myogenesis, TGFβ activates SMAD2 and SMAD3 and functions to inhibit myogenic differentiation; these SMADs are therefore considered to be anti-myogenic. Now, Nadine Wiper-Bergeron and colleagues report that, in the absence of TGFβ, SMAD2 can in fact promote terminal myogenic differentiation. They first show that SMAD2 expression in the C2C12 cell line is regulated during myogenic differentiation and that its overexpression enhances terminal differentiation and myoblast fusion. Following on from this, the researchers demonstrate that primary mouse myoblasts deficient for Smad2 exhibit impaired myotube maturation and reduced levels of the myogenic regulatory factor, myogenin. The authors also reveal that knockdown of SMAD2 in muscle stem cells (satellite cells) in vivo inhibits muscle regeneration after injury. Finally, they report that SMAD2 positively regulates the expression of the pro-fusogenic genes Klf4 and Npnt, whilst negatively regulating the expression of inhibitors of myogenic differentiation. Together, these findings uncover a new role for SMAD2 as a key regulator of myogenic differentiation and fusion, and also highlight functions for SMAD2 beyond classical TGFβ signalling.
