Deficiency of muscular dystrophy-related gene JAG2 causes NOTCH signaling dysfunction in muscle stem cells - PubMed
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- #muscle stem cells
- #muscular dystrophy
- #NOTCH signaling
- A deficiency in the muscular dystrophy-related gene JAG2 leads to NOTCH signaling dysfunction in muscle stem cells (MuSCs).
- Studies using mouse and fly models, along with in vitro analyses, show that both Jag2 deficiency and pathogenic JAG2 variants impair NOTCH signaling, affecting myogenic self-renewal and differentiation.
- Hypomorphic Jag2 mutant mice exhibit depleted MuSCs and impaired muscle regeneration, highlighting the role of JAG2 in muscle repair.
- Co-culture and conditional knockout experiments reveal that MuEC-specific Jag2 knockout reduces MuSC self-renewal, while MuSC-specific knockout hinders myogenic differentiation.
- Human pathogenic JAG2 variants fail to rescue deficiency in the Drosophila ortholog Serrate, indicating these variants disrupt function and signaling pathways.
- Pathogenic JAG2 variants impair muscle development and regeneration through disrupted cis-inhibition and trans-activation of NOTCH signaling.
- Optimizing JAG2-mediated NOTCH signaling is identified as a potential therapeutic approach for JAG2-related muscular dystrophy.