JAG1

JAG1 is a human gene that encodes Jagged-1, a transmembrane ligand of the Notch receptor family. Jagged-1 is part of the Delta/Serrate/LAG-2 (DSL) family and participates in Notch signaling, a conserved pathway that governs cell fate decisions during embryonic development and tissue maintenance.

The JAG1 gene produces a type I transmembrane protein with an extracellular region containing a DSL domain and multiple epidermal growth factor-like repeats. Jagged-1 binds Notch receptors (Notch1–Notch4) on adjacent cells, triggering proteolytic cleavages of the receptor and release of the Notch intracellular domain. The NICD moves to the nucleus and, with RBPJ and coactivators, regulates transcription of target genes such as HES and HEY, influencing differentiation, proliferation, and boundary formation.

JAG1 expression is developmentally regulated and prominent in developing liver, heart, and vasculature. Jagged-1–Notch signaling is essential for bile duct formation, cardiac morphogenesis, and vascular remodeling. Disruptions in this signaling can perturb organogenesis and postnatal tissue homeostasis, contributing to disease.

Clinical significance: Mutations in JAG1 cause Alagille syndrome (arteriohepatic dysplasia), an autosomal dominant disorder characterized by paucity of intrahepatic bile ducts, cholestasis, distinctive facial features, vertebral anomalies, and congenital heart defects. The phenotype shows variable expressivity and penetrance. NOTCH2 mutations can produce a clinically similar presentation. In addition to developmental disease, altered JAG1/Notch signaling has been linked to cancers and vascular disorders, reflecting its role in cell communication and angiogenesis.

Research and therapy: Understanding JAG1-Notch signaling informs potential therapeutic strategies that modulate Notch activity, though clinical applications are complex due to pathway ubiquity and context-dependent effects.