Vgll3 is up-regulated during muscle regeneration, regulates muscle differentiation ex vivo and is highly expressed in human alveolar rhabdomyosarcoma (ARMS)

Vgll1-4 (also known as Vito’s) bind Tead1-4 transcription factors through their Tondu domain at the same site where Yap binds (Pobbati et al., 2012). Intriguingly the expression of the ARMS fusion gene PAX3-FOXO1 increases Vgll3 expression 8.41-fold in the developing chick limb (Lagha et al., 2010). Consistent with this, Vgll3 expression is highest in PAX3-FOXO1-positive ARMS when compared to other types of rhabdomyosarcoma and differentiated skeletal muscle. Vgll3 expression increases more than 30-fold between day 3-5 post injury of mouse tibialis anterior muscle. VGLL3 overexpression alters gene expression in a way that suggests that VGLL3 is a YAP antagonist. VGLL3 overexpression in myoblasts enhances myogenic differentiation, which is antagonistic to YAP1 S127A, which blocks differentiation. Together these data suggest that Vgll3 is a Pax3-regulated Yap antagonist in the muscle lineage that might contribute to the pathogenesis of ARMS.