Meckel's Cartilage and Mandibles: Effects of the Fgfr2 C342Y mutation on development of the lower jaw in a Crouzon syndrome mouse model.

The Fgfr2cC342Y/+ Crouzon syndrome mouse model carries a cysteine to tyrosine substitution at amino acid position 342 (Cys342Tyr; C342Y) in fibroblast growth factor receptor 2 (FGFR2), equivalent to the FGFR2 mutation commonly associated with Crouzon syndrome. Crouzon syndrome is an autosomal dominant condition characterized by craniofacial anomalies. The FGFR2 C342Y mutation results in constitutive activation of the receptor and is associated with up-regulation of osteogenic differentiation. Although premature closure of the coronal suture is the focus of most studies of Crouzon syndrome, cartilage elements of the skull are also known to be affected by this mutation. Fgfr2cC342Y/+ Crouzon syndrome mice commonly exhibit malocclusion of the jaws, most likely due to abnormal craniofacial form. The current paradigm of mandibular development assumes Meckel's cartilage (MC) provides a model for mandibular development. Malformation of the mandible can precipitate a plethora of complications including disrupting development of the upper jaw and the palate, impediment of the airway, as well as altering the functional occlusion necessary for proper mastication. Here we investigate the relationship of Meckel's cartilage to mandible development. Using Fgfr2cC342Y/+ Crouzon syndrome mice and their unaffected littermates (Fgfr2c+/+ mice) at embryonic days 15.5 and 17.5 we explore the form of Meckel's cartilage and the developing mandible as Meckel's cartilage begins to degrade. A histological assessment of the chondrocytes within Meckel's cartilage reveals few differences in cell size between genotypes at either timepoint, however there are more chondrocytes present in the most anterior aspects of the cartilage in Fgfr2cC342Y/+ mice at E15.5. No differences between genotypes were found in osteoblast (ALP) or osteoclast (TRAP) activity of the mandibles at E15.5 but osteoclast activity was greater in unaffected Fgfr2c+/+ mice at E17.5. These data reveal that further investigation of Crouzon syndrome mice can uncover differential effects of the C342Y mutation in FGFR2 in cells other than those surrounding the coronal suture.