Jagged1 functions downstream of Twist1 in the specification of the coronal suture and the formation of a boundary between osteogenic and non-osteogenic cells

Restricted until 20 Nov. 2010. In this dissertation, I would like to address how the evolutionarily conserved Notch signaling molecules regulate the formations of murine cranial bones and sutures. Mutations in the Notch ligand, JAGGED1, cause Alagille syndrome, which has craniosynostosis as a feature. The expression pattern of Jagged1 at mouse coronal suture suggested that it might play a role in establishing boundary between osteogenic and non-osteogenic cells. Tissue-specific knockout of Jagged1 in mouse mesoderm affected the expression of downstream Notch signaling at sutural cells and resulted in craniosynostosis. Immunostaining results also implied that the boundary between presumptive cranial bones has been established by Notch signaling at early stage, while the opposing osteogenic fronts of the bones are still far away from each other. I further demonstrated the genetic interactions between Notch signaling and Twist1 which is animportant pathogenic gene in regulating cranial sutures morphogenesis. Twist1 regulates Notch signaling in sutural mesenchyme and maintain suture patency. The phenotypic studies of mouse skulls and middle ear ossicles indicated that Jagged1 interacts functionally with Twist1 in several distinct developmental settings. This work reveals a molecular network that controls cranial development, and establishes a new model of boundary formation at developing cranial suture.