Cdkn1c drives muscle differentiation through a positive feedback loop with Myod

Differentiation often requires conversion of analogue signals to a stable binary output through positive feedback. Hedgehog (Hh) signalling promotes myogenesis in the vertebrate somite, in part by raising the activity of muscle regulatory factors (MRFs) of the Myod family above a threshold. Hh is known to enhance MRF expression. Here we show that Hh is also essential at a second step that increases Myod protein activity, permitting it to promote Myogenin expression. Hh acts by inducing expression of cdkn1c (p57Kip2) in slow muscle precursor cells, but neither Hh nor Cdkn1c is required for their cell cycle exit. Cdkn1c co-operates with Myod to drive differentiation of several early zebrafish muscle fibre types. Myod in turn up-regulates cdkn1c, thereby providing a positive feedback loop that switches myogenic cells to terminal differentiation. ► Myod and Cdkn1c (p57Kip2) interact genetically to promote myogenesis. ► Cdkn1c expression is Hedgehog-dependent in zebrafish adaxial cells. ► Cdkn1c promotes Myod protein accumulation. ► MRFs maintain Cdkn1c expression in vivo, thereby creating a positive feedback loop. ► Cdkn1c is not required for adaxial cell cycle exit, but to drive differentiation.