Deficiency of muscular dystrophy-related gene JAG2 causes NOTCH signaling dysfunction in muscle stem cells.

We previously identified a muscular dystrophy caused by biallelic variants in JAGGED2 (JAG2), whose protein product, JAG2, is a canonical NOTCH ligand. However, the disease mechanism remains unclear, particularly with respect to muscle stem cell (muscle satellite cell/MuSC) function and muscle regeneration. We examined the consequences of JAG2 deficiency and modeled pathogenic JAG2 variants in vitro and in vivo, the latter in mouse and fly models and with particular attention to the MuSC-muscle endothelial cell (MuEC) niche. We found that both Jag2 deficiency and overexpression of pathogenic JAG2 variants impaired NOTCH signaling and myogenic self-renewal and differentiation. Hypomorphic Jag2 mutant (Jag2sm) mice displayed depleted MuSCs, corresponding with impaired muscle regeneration in those mice. Coculture experiments and the examination of cell type-specific Jag2 conditional knockout mice demonstrated that MuEC-specific Jag2 knockout resulted in reduced MuSC self-renewal, while MuSC-specific Jag2 knockout resulted in reduced myogenic differentiation. Human reference JAG2, but not human pathogenic variants of JAG2, rescued the deficiency of Serrate, the Drosophila ortholog of JAG2. Therefore, pathogenic variants in JAG2 impair muscle development and regeneration through disrupted cell-autonomous cis-inhibition and nonautonomous trans-activation involving NOTCH signaling dysfunction. Our findings indicate that optimizing JAG2-mediated NOTCH signaling is a potential therapeutic approach for JAG2-related muscular dystrophy.