Abnormalities in Cartilage in Embryonic Fgfr2c C342Y/+ Crouzon Syndrome Mice

Abstract

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, particularly within the braincase floor have also been described as anomalous. The Fgfr2cC342Y/+ 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. Skeletogenesis of the skull and facial bones which are affected in these mice is preceded by development of the chondrocranium, a cartilaginous skull whose elements either disappear, remain as cartilage, or ossify endochondrally. Consequently, normal growth and development of the skull relies on appropriate chondrocyte activity including controlled proliferation. We analyzed proliferative activity of chondrocytes of the braincase floor and vomeronasal region of E14.5 and E15.5 Fgfr2cC342Y/+ mice and unaffected littermates to determine the effects of the mutation on the proliferation of chondrocytes. Relative to chondrocytes of unaffected littermates, chondrocytes of Fgfr2cC342Y/+ mice are delayed in proliferative potential as there is less proliferation in mutant chondrocytes of the braincase floor (p≤0.001) and para-septal cartilages (p≤0.001) at E14.5 and more proliferation at E15.5 (para-septal cartilage p≤0.001). There are no statistically significant differences in proliferative potential within the nasal septum at either age investigated. Disruption to the tightly regulated developmental processes in the chondrocranium can have significant and lasting effects on craniofacial development. Thus, expanding this investigation with additional developmental ages will help ascertain how the function of this FGFR mutation in embryonic cartilage contributes to the abnormal craniofacial form associated with Crouzon Syndrome.