Negative regulation of Jagged1 by glycosylation: towards a mechanism-based therapy for Alagille syndrome

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Summary Notch signaling is a cell-to-cell communication mechanism critical for embryonic development and adult homeostasis. To communicate information between cells, Notch receptors on a given cell need to be activated by ligands from neighboring cells. One of the Notch pathway ligands with broad biological roles is called jagged1. Heterozygosity for the jagged1 gene in humans results in Alagille syndrome, which is a multisystem developmental disorder characterized by bile duct abnormalities and defects in other organs systems including the cardiovascular system, kidney and skeleton. The clinical presentation of Alagille syndrome is extremely variable, even in patients with identical point mutations. Accordingly, it has been proposed that genetic modifiers play an important role in the pathophysiology of this disease. Moreover, no mechanism-based treatment has yet been established for Alagille syndrome. We have recently reported a mouse model for Alagille syndrome and have identified the glycosyltransferase gene Poglut1 as a dominant genetic suppressor of the phenotypes in this model. In this proposal, we will use biochemical and cell culture assays, transcriptional profiling and mouse genetic experiments to determine the mechanism of jagged1 regulation by glycosylation and to identify critical targets of jagged1 during bile duct development. We will also use our preliminary data and mouse model as a basis to establish a potential therapeutic approach for Alagille syndrome. These studies have the potential to provide novel insight into the pathophysiology of this disease and the molecular mechanisms underlying the regulation of jagged1-mediated signaling by glycosylation.