Differential Effects of the Fgfr2c C342Y Mutation on Developing Cranial Cartilage.

Crouzon syndrome is an autosomal dominant condition characterized by craniofacial anomalies in the absence of major hand and foot abnormalities. Although premature closure of the coronal suture is the focus of most studies of Crouzon syndrome, cartilage elements have also been described as anomalous. The Fgfr2c Crouzon syndrome mouse model carries a cysteine to tyrosine substitution at amino acid position 342 (Cys342Tyr; C342Y) in Fgfr2, equivalent to one of the FGFR2 mutations commonly associated with Crouzon syndrome. This mutation results in constitutive activation of the receptor and is associated with up-regulation of osteogenic differentiation and consequent skull deformities. Development of the bony skull of these mice is known to be affected, but is preceded by development of the chondrocranium, a cartilaginous skull whose elements either disappear, remain as cartilage, or ossify endochondrally. In conjunction with identified disparities in the size and shape of the chondrocranium between Fgfr2c mice and unaffected Fgfr2c littermates throughout development, we analyzed the morphology and proliferative activity of chondrocytes of the nasal septum (mostly remains as cartilage), braincase floor (ossifies endochondrally), and lateral walls (disappears) of the chondrocranium at embryonic day 14.5 (E14.5) and E15.5 to determine the effects of the mutation on cartilage cells. Consistent with a larger chondrocranium, Fgfr2c mice had relatively more chondrocytes in the nasal septum (p≤0.01) and lateral wall (p≤0.001) at E14.5. At E15.5 there were more chondrocytes in the lateral wall (p≤0.001) of Fgfr2c chondrocrania, but the cells of the lateral wall in Fgfr2c mice were larger (p≤0.001) than in control (Fgfr2c ) mice at both timepoints. There were no differences between genotypes in either chondrocyte number or size in the braincase floor, however more proliferative activity was identified in Fgfr2c braincase floors at E14.5 (p≤0.001). No differences in proliferation were identified between genotypes in either the nasal septum or the lateral walls. Our data indicate that regions of the chondrocranium are differentially affected by the Fgfr2c C342Y mutation, potentially based on the fate of each cartilage. Disruption to the tightly regulated developmental processes of the chondrocranium including cell proliferation and hypertrophy can have significant and lasting effects on craniofacial development through direct effects on cartilage formation and the indirect effects of chondrocranial morphology on development of bone.