Jag1, also known as Jagged1, is one of the 5 cell surface ligands functioning primarily in the highly conserved Notch signaling pathway. This pathway plays a critical role in cellular fate determination, being active throughout development and across many organ systems. The classic Jag1-NOTCH interaction leads to a cascade of proteolytic cleavages, ultimately activating downstream transcription of target genes [2].

In atherosclerosis, disturbed blood flow activates the JAG1-NOTCH4 signaling pathway. EC-specific genetic deletion of Jag1 (Jag1ECKO) demonstrated that Jag1 promotes atherosclerosis at sites of disturbed flow by suppressing subsets of proliferating and migrating endothelial cells [1]. In Alagille syndrome, a multi-system disorder, loss-of-function mutations in Jag1 are the main cause, indicating haploinsufficiency for Jag1 in relevant tissues [2]. Also, in the context of liver fibrosis in Alagille syndrome, Jag1 insufficiency in Jag1Ndr/Ndr mice led to immature hepatocytes, low intra-hepatic T cell infiltration, and an altered fibrotic process [3].

In conclusion, Jag1 is crucial in the Notch signaling pathway, playing important roles in processes like cellular fate determination. Studies using gene-knockout mouse models, such as Jag1ECKO and Jag1Ndr/Ndr mice, have revealed its role in diseases like atherosclerosis and Alagille syndrome, including associated liver fibrosis. These models have provided valuable insights into the disease mechanisms related to Jag1, facilitating a better understanding of the biological functions of Jag1 in disease contexts.