Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients

JAGGED1 mutations cause Alagille syndrome, comprising a constellation of clinical findings, including biliary, cardiac and craniofacial anomalies. Jagged1, a ligand in the Notch signaling pathway, has been extensively studied during biliary and cardiac development. However, the role of JAGGED1 during craniofacial development is poorly understood. Patients with Alagille syndrome have midface hypoplasia giving them a characteristic 'inverted V' facial appearance. This study design determines the requirement of Jagged1 in the cranial neural crest (CNC) cells, which encompass the majority of mesenchyme present during craniofacial development. Furthermore, with this approach, we identify the autonomous and non-autonomous requirement of Jagged1 in a cell lineage-specific approach during midface development. Deleting Jagged1 in the CNC using Wnt1-cre; Jag1 Flox/Flox recapitulated the midfacial hypoplasia phenotype of Alagille syndrome. The Wnt1-cre; Jag1 Flox/Flox mice die at postnatal day 30 due to inability to masticate owing to jaw misalignment and poor occlusion. The etiology of midfacial hypoplasia in the Wnt1-cre; Jag1 Flox/Flox mice was a consequence of reduced cellular proliferation in the midface, aberrant vasculogenesis with decreased productive vessel branching and reduced extracellular matrix by hyaluronic acid staining, all of which are associated with midface anomalies and aberrant craniofacial growth. Deletion of Notch1 from the CNC using Wnt1-cre; Notch1 F/F mice did not recapitulate the midface hypoplasia of Alagille syndrome. These data demonstrate the requirement of Jagged1, but not Notch1, within the midfacial CNC population during development. Future studies will investigate the mechanism in which Jagged1 acts in a cell autonomous and cell non-autonomous manner.