UCSF

Alagille Syndrome is a multisystem genetic disorder characterized by chronic cholestasis,cardiovascular anomalies, ocular abnormalities, skeletal defects, and characteristic facial features. Mutations in Jagged1 (Jag1), a key ligand in the Notch signaling pathway, are associated with the majority of cases. The Notch signaling pathway plays important roles in the development and homeostasis of most, if not all tissues. However, the roles of Jag1 and the Notch signaling pathway in craniofacial and dental development remain unclear. This study aimed to elucidate the roles of Notch signaling pathway in craniofacial and dental development using a mouse model of Alagille Syndrome (Jag1Ndr/Ndr mice, which possess a missense mutation (H268Q) in Jag1). Embryonic and postnatal mouse specimens were collected at various stages from Jag1Ndr/Ndr mice. Micro-computed tomography (microCT) and three-dimensional (3D) Geometric Morphometric Analysis (GMA) were performed on adult skulls to analyze changes in craniofacial morphology. Hematoxylin and eosin (H&E) staining on histological sections was performed on control and Jag1Ndr/Ndr mice at embryonic day (E)14.5, E16.5, postnatal (P)0, and P7 to analyze tooth development. 3D GMA showed variations in the coronoid process, zygomatic process, and the area where parietal, occipital, and squamosal bones intersect in Jag1Ndr/Ndr mutant mice. In addition, mutants had more convex crania from both frontal and lateral views and a longer snout. Our histological analysis of tooth development showed defects in cell-matrix adhesion (ameloblast-enamel matrix) and cell-cell adhesion (ameloblast-stratum intermedium) at P7. MicroCT analysis of P7 and adult molars supported our histological findings and revealed changes in tooth morphology. Disruption in Notch signaling due to a missense mutation (H268Q) in Jag1 led to: 1) specific changes in craniofacial morphology; 2) defective cell-matrix and cell-cell attachments during tooth development; 3) possible changes in tooth structures due to abnormal tooth development and mineralization. Our study demonstrates for the first time that Notch signaling is essential for specific changes in craniofacial morphology and proper dental development.