Regulation of skeletal myogenesis by Notch

Abstract

Notch signaling has emerged as a key player in skeletal muscle development and regeneration. Simply stated, Notch signaling inhibits differentiation. Accordingly, fine-tuning the pathway is essential for proper muscle homeostasis. This review will address various aspects of Notch signaling, including our current views of the core pathway, its effects in muscle, its interactions with other signaling pathways, and its relationship with ageing.

Fig. 1

Schematic representation of Notch signaling in myoblasts and its interactions with other pathways. CSL interacts with transcriptional corepressors (CoR) in the absence of signaling and with coactivators, including Mastermind (MAML), when bound by NICD. This process is enhanced by the binding of Smad proteins (activated by TGFß), Hif1α (stabilized by hypoxia) and Foxo1 (inactivated by Insulin). Relevant gene targets include those encoding Hey1, MyoR and possibly many others. Protein products of the Notch target genes repress transcription of pro-myogenic genes, shown here to be activated by MyoD and Mef2C, through multiple mechanisms, including targeted repression by Hey1.

Fig. 2

Points of control exerted by Notch signaling during muscle regeneration. Notch has been implicated in 1) the cell fate choice that governs the progression of muscle stem cells to committed progenitors and 2) the proliferation of progenitors prior to terminal differentiation into myotubes.