JAG1Notch

Jagged1 (JAG1) is a transmembrane ligand of the Notch family of signaling receptors and is encoded by the JAG1 gene located on chromosome 20q12. JAG1 binds to Notch receptors on adjacent cells, triggering proteolytic cleavage and release of the Notch intracellular domain, which translocates to the nucleus to regulate transcription of target genes involved in cell fate, proliferation, differentiation and apoptosis.

During embryogenesis, JAG1–Notch signaling is essential for the development of the heart, kidneys, lungs, and blood vessels. In the cardiovascular system, JAG1 promotes the formation of the coronary vasculature and maintains vascular smooth muscle cell integrity. In the nervous system, it regulates neuronal differentiation and glial cell specification, while in hematopoietic tissues it modulates stem cell maintenance and differentiation of myeloid lineages.

JAG1 expression is tightly controlled at transcriptional, post‑transcriptional and post‑translational levels. MicroRNAs, such as miR‑125b, can dampen JAG1 mRNA, whereas glycosyltransferases that modify Notch receptors influence ligand binding affinity. In addition, alternative splicing of the JAG1 transcript generates isoforms with distinct signaling potency and cellular localization.

Mutations in JAG1 underlie Alagille syndrome, a multisystem disorder characterized by bile duct paucity, cardiac malformations, skeletal anomalies, ocular defects, and immunological abnormalities. Pathogenic variants generally lead to haploinsufficiency or dominant negative effects that reduce functional ligand availability. In oncology, aberrant JAG1 upregulation has been reported in breast, prostate and colorectal cancers, where it can drive tumor growth, angiogenesis and therapeutic resistance by sustaining Notch signaling.

Researchers study JAG1–Notch interactions to elucidate developmental biology, repair mechanisms and potential therapeutic targets for congenital diseases, fibrosis, and cancer. Ongoing clinical trials aim to inhibit or modulate JAG1 activity using monoclonal antibodies, soluble decoys, or gene‑editing approaches, with the goal of ameliorating disease phenotypes while preserving essential physiological processes.