RhoA and ERK signalling regulate the expression of the myogenic transcription factor Nfix

Abstract

The transcription factor Nfix belongs to the nuclear factor one family and has an essential role in prenatal skeletal muscle development, where it is a master regulator of the transition from embryonic to foetal myogenesis. Recently, Nfix was shown to be involved in adult muscle regeneration and in muscular dystrophies. Here, we investigated the signalling that regulates Nfix expression, and show that JunB, a member of the AP-1 family, is an activator of Nfix, which then leads to foetal myogenesis. Moreover, we demonstrate that their expression is regulated through the RhoA/ROCK axis, which maintains embryonic myogenesis. Specifically, RhoA and ROCK repress ERK kinase activity, which promotes JunB and Nfix expression. Notably, the role of ERK in the activation of Nfix is conserved post-natally in satellite cells, which represent the canonical myogenic stem cells of adult muscle. As lack of Nfix in muscular dystrophies rescues the dystrophic phenotype, the identification of this pathway provides an opportunity to pharmacologically target Nfix in muscular dystrophies.