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 [2]. The classic Jag1-NOTCH interaction triggers a cascade of proteolytic cleavages, leading to the activation of downstream transcription of target genes.

In mouse models, EC-specific genetic deletion of Jag1 (Jag1ECKO) showed that Jag1 promotes atherosclerosis at sites of disturbed blood flow, as it suppresses subsets of endothelial cells (ECs) that proliferate and migrate [1]. In Jag1Ndr/Ndr mice, a model for Alagille syndrome (ALGS), there are immature hepatocytes, low intrahepatic T cell infiltration, and altered liver fibrosis, indicating that Jag1-dependent hepatic and immune defects interact to determine the fibrotic process in ALGS [3]. Conditional knockout and knockin of Hoxa5 in mouse kidney proximal tubules demonstrated that HOXA5 represses Jag1 transcription, affecting kidney fibrosis [4].

In conclusion, Jag1 is crucial in the Notch signaling pathway, influencing cellular fate determination. Gene-knockout mouse models have revealed its role in diseases like atherosclerosis, Alagille syndrome, and kidney fibrosis. These findings enhance our understanding of disease mechanisms related to Jag1, potentially guiding future therapeutic strategies.

References:

1. Souilhol, Celine, Tardajos Ayllon, Blanca, Li, Xiuying, Serbanovic-Canic, Jovana, Evans, Paul C. 2022. JAG1-NOTCH4 mechanosensing drives atherosclerosis. In Science advances, 8, eabo7958. doi:10.1126/sciadv.abo7958. https://pubmed.ncbi.nlm.nih.gov/36044575/

2. Grochowski, Christopher M, Loomes, Kathleen M, Spinner, Nancy B. 2015. Jagged1 (JAG1): Structure, expression, and disease associations. In Gene, 576, 381-4. doi:10.1016/j.gene.2015.10.065. https://pubmed.ncbi.nlm.nih.gov/26548814/

3. Mašek, Jan, Filipovic, Iva, Van Hul, Noémi, Dobeš, Jan, Andersson, Emma R. 2024. Jag1 insufficiency alters liver fibrosis via T cell and hepatocyte differentiation defects. In EMBO molecular medicine, 16, 2946-2975. doi:10.1038/s44321-024-00145-8. https://pubmed.ncbi.nlm.nih.gov/39358604/

4. Xiao, Xiao, Wang, Wei, Guo, Chunyuan, Chen, Jiankang, Dong, Zheng. 2024. Hypermethylation leads to the loss of HOXA5, resulting in JAG1 expression and NOTCH signaling contributing to kidney fibrosis. In Kidney international, 106, 98-114. doi:10.1016/j.kint.2024.02.023. https://pubmed.ncbi.nlm.nih.gov/38521405/