Toward an understanding of nonsyndromic craniosynostosis: Altered patternsof TGF-beta receptor and FGF receptor expression induced by intrauterine head constraint

Although the etiology of nonsyndromic forms of craniosynostosis remains unc ertain, recent experiments from our laboratory have demonstrated that fetal head constraint induces cranial suture fusion in mice through a process as sociated with altered patterns of transforming growth factor beta (TGF-beta ) isoform expression. Other recent studies have highlighted the role of sec reted signaling molecules, including members of the TGF-beta superfamily an d the fibroblast growth factors (FGFs), as well as their receptors, in regu lating suture development and fusion, The purpose of these experiments was to examine the potential role of TGF-beta receptors and FGF receptor 2 (FGF R2) in nonsyndromic craniosynostosis by determining their temporospatial pa tterns of expression during development complicated by intrauterine head co nstraint. This study consisted of two groups of C57Bl/6J mice: an experimen tal group subjected to intrauterine constraint and a control unconstrained group. Fetal head constraint was induced by performing uterine cerclage on day 17.5 of gestation and allowing intrauterine fetal growth to continue 24 and 48 hours beyond the normal gestational period. Control animals underwe nt hysterotomy on day 17.5 and the nonconstrained pups were allowed to cont inue intra-abdominal fetal growth 48 hours beyond normal gestation. Express ion of TGF-beta receptor types I and II, and FGFR2 in the calvarial tissue was determined by immunohistochemical analysis. In the unconstrained contro l animals, there was minimal immunoreactivity for both TGF-P receptors and FGFR2 within the coronal suture. After 24 hours of constraint, however, the re was a marked increase in immunoreactivity of TGF-beta receptors and FGFR 2 in the osteoblasts along the osteogenic fronts and in the dural cells. Af ter 48 hours, there was continued expression of both type I and type II rec eptors and FGFR2 within the midsutural mesenchyme of the coronal suture, in the osteoblasts, and in the dura. The authors demonstrated substantial upr egulation of TGF-beta receptor types I and II and FGFR2 in coronal sutures subjected to in utero constraint. These results suggest an important role f or TGF-beta /TGF-beta receptor, and FGF/FGFR signaling in the pathogenesis of constraint-induced craniosynostosis.