JAG2

JAG2, also known as Jagged2, is a gene that encodes a transmembrane ligand in the Delta/Serrate/Lag-2 (DSL) family of Notch ligands. Jagged2 binds to Notch receptors on neighboring cells and activates Notch signaling, initiating proteolytic cleavages of the receptor and release of the Notch intracellular domain, which travels to the nucleus to regulate transcription of target genes such as the Hes and HEY families. The Jagged2 protein consists of a DSL domain, multiple epidermal growth factor-like repeats, and a single-pass transmembrane region, enabling cell–cell contact–dependent signaling.

Expression of JAG2 is dynamic during development, with broad but tissue-specific patterns in the embryo. It plays roles in multiple organ systems, including cardiac, craniofacial, neural, and limb development, where Notch signaling decisions influence cell fate, differentiation, and morphogenesis. As with other Notch ligands, Jagged2 can function as an activator of Notch signaling in one cellular context and modify signaling strength in another, depending on receptor availability and interactions with other ligands.

Clinical significance: Human JAG2 variants have been reported in a subset of individuals with congenital anomalies, often with features overlapping Notch pathway–related disorders. In particular, JAG2 mutations or haploinsufficiency have been described in Alagille syndrome–like phenotypes, though JAG1 mutations remain the predominant cause. Copy number changes involving JAG2 have also been observed in craniofacial and developmental anomalies. Overall, the contribution of JAG2 to disease is variable and ongoing research continues to clarify its role.

Evolution and orthologs: JAG2 is conserved across vertebrates, with Jagged2 orthologs studied in mice, zebrafish, and other model organisms, reflecting the preserved role of Notch signaling in development.