Pleiotropic features of syndromic craniosynostoses correlate with differential expression of fibroblast growth factor receptors 1 and 2 during human craniofacial development

Mutations in FGFR1, -2, and -3 are linked to five human craniosynostosis sy ndromes. In addition to premature fusion of cranial sutures, nonskeletal ma nifestations in skin, and teeth together with CNS abnormalities, reflect wi despread effects of these mutations. To understand this pleiotropy, we have assessed craniofacial FGFR1 and -2 expression in the human embryo from 6 w k postfertilization. We found that both genes are expressed in sheets of co ndensed mesenchyme before overt chondrogenic differentiation and that disti nct patterns of expression are established by 8 wk. Thus, FGFR2(BEK) is exp ressed evenly throughout developing cartilage and bone, whereas FGFR1 trans cripts predominate in perichondria and periostea. Complementary patterns of FGFR1 and FGFR2(BEK and KGFR) expression are also observed in the enamel e pithelium and papilla mesenchyme of the tooth germ, at a stage when morphog enetic tissue interactions ensue. Both genes are expressed in the cortical layer of the brain, but expression levels vary significantly within the cho roid plexus and wall of the fourth ventricle. Similarly, tissue-specific di fferences in receptor expression are found in both the skin and salivary gl ands. These expression data are consistent with the pleiotropic manifestati ons of syndromic craniosynostoses and provide the basis for a new paradigm to explain the associated CNS problems.