Neural crest specific ablation of Jagged1 results in aberrant osteoblast differentiation and maxillary bone development

Abstract

Maxillary hypoplasia results from insufficient growth of the upper jaw bone which affects mastication, respiration and communication. This results from either extrinsic restriction due to premature cranial base suture fusion (eg Apert Syndrome) or from intrinsic growth deficiency of the maxilla (eg Alagille Syndrome). The maxillary bone is formed through intramembranous ossification of neural crest cell derived mesenchyme. Conditional deletion of Jagged1 in the cranial neural crest cells (CNC) using Wnt1‐Cre (Jag1CKO) recapitulated the maxillary hypoplasia phenotype in Alagille Syndrome patients, who have JAGGED1 mutations. Jag1CKO mice die by P21 due to starvation secondary to severe maxillary hypoplasia. Analysis of the maxilla using qPCR and immunohistochemistry on Jag1CKO mice from e14 to e18 revealed reduced expression of early and late markers of osteoblast differentiation. In vitro bone mineralization cultures demonstrated that Jag1CKO maxillary mesenchymal cells have decreased mineralization potential and a diminished induction of osteoblast differentiation markers. In addition, lack of Jagged1 signaling in the maxilla resulted in disregulated BMP and TGFβ signaling pathways. These data suggest that Jagged1 signaling in CNC is required during osteoblast differentiation and that down‐stream targets of Jagged1 signaling include the BMP and TGFβ pathways.