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 JAG2 , whose protein product Jagged2 JAGGED2 (JAG2) is a canonical Notch NOTCH ligand. However, the disease mechanism remains unclear, particularly with respect to muscle stem 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 NOTCHNotch signaling and myogenic self-renewal and differentiation. Hypomorphic Jag2 mutant ( Jag2 sm ) mice display depleted MuSCs, corresponding with impaired muscle regeneration in those mice. Co-culture 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 ( Ser ), the Drosophila ortholog of JAG2 . Therefore, pathogenic variants in JAG2 impair muscle development and regeneration through disrupted cell-autonomous cis -inhibition and non-autonomous trans-activation involving NOTCHNotch signaling dysfunction. Our findings indicate that optimizing JAG2-mediated NOTCHNotch signaling is a potential therapeutic approach for JAG2 -related muscular dystrophy.