Fig. 7.

Proposed model of mandibular dysmorphogenesis in prenatal development of Fgfr2^+/S252W mice. In the mandible of Fgfr2^+/+ mice, FGFR2 signaling is activated by specific FGF binding, forming a complex of FGFs, heparan sulfate and FGFRs. The linker region between the immunoglobulin-like domains II and III regulates the ligand binding specificity and affinity. Dimerization and transphosphorylation by kinases in the intracellular domain of FGFR2 cause activation of downstream signaling cascades. These activated signaling pathways can regulate gene expression, controlling osteogenesis, osteoclastogenesis and chondrogenesis. Transcriptional level: The FGFR2 S252W mutation alters ligand specificity and affinity, resulting in abnormal FGFR2 signaling, which dysregulates the transcriptome in different cell types. Tissue level: Osteoblast proliferation is activated, enlarging the osteogenic tissue. Increased PPi inhibits mineralization, and bone resorption is promoted through osteoclastic activity, causing a change in the microarchitecture. Meckel’s cartilage is affected by increased proliferation of chondrocytes, resulting in an increase in size. Morphological level: Abnormal osteogenic activities contribute to changes in mandibular shape.