Jagged1 (JAG1) is one of five cell surface proteins (ligands) that interact with four receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fate decisions in many organ systems. Once the JAG1-NOTCH (receptor-ligand) interactions take place, a cascade of proteolytic cleavages is triggered resulting in activation of the transcription for downstream target genes. Located on human chromosome 20, the JAG1 gene is expressed in multiple organ systems in the body and causes the autosomal dominant disorder Alagille syndrome (ALGS) resulting from loss of function mutations within the gene. JAG1 has also been designated as CD339 (cluster of differentiation 339).
Structure and function
JAG1 was first identified as a ligand that was able to activate notch receptors when it was cloned in the mammalian rat in 1995. It is located at cytogenetic location 20p12.2 and genomic location (GRCh37) chr20:10,618,331-10,654,693 on the human chromosome 20. The structure of the JAG1 protein includes a small intracellular component, a transmembrane motif, proceeded by an extracellular region containing a cystine-rich region, 16 EGF-like repeats, a DSL domain, and finally a signal peptide totaling 1218 amino acids in length over 26 coding exons.
The JAG1 protein encoded by JAG1 is the human homolog of the Drosophila jagged protein. Human JAG1 is one of five ligands for receptors in the NOTCH signaling pathway which helps to determine cellular fate and is active during many developmental stages. The extracellular component of the JAG1 protein physically interacts with its respective Notch receptor. This interaction kicks off a cascade of proteolytic cleavages leading to the original NOTCH intracellular domain being trafficked into the nucleus of the cell leading to the activation of different target genes.
Expression profile and mouse studies
In situ hybridization and conditional gene knockout studies have helped to demonstrate the role JAG1 plays in development and its effects on different organ systems. In humans, JAG1 has broad expression in many tissue types including the pancreas, heart, placenta, prostate, lung, kidney, thymus, testis, and leucocytes in the adult. In a developing embryo JAG1 expression is concentrated around the pulmonary artery, mesocardium, distal cardic outflow tract, major arteries, metanephros, branchial arches, pancreas, the portal vein, and otocyst. Generally, JAG1 expression patterns correlate with organ systems affected in ALGS, although it is important to note that not all tissues where JAG1 is expressed are affected in ALGS. More recently JAG1 expression has been found to be altered in breast cancer and adrenocortical carcinoma patients.
Mouse models where the Jag1 gene is turned off in certain tissues (conditional knockout mouse models) have been used to study the role of Jag1 in many tissue specific areas. While homozygous deletions of Jag1 have been shown to be embryonic lethal in mice, and heterozygous deletions may show only a limited phenotype (involving the eye), mice haploinsufficient for both Jag1 and Notch2 present with the ALGS phenotype. Conditional gene knockout mouse models with Jag1 mutations targeted to the portal vein mesenchyme, endothelium, and cranial neural crest all exhibit features classic to those in individuals with ALGS, highlighting the role of this tissue type in disease origins
