The development of the craniofacial skeleton with its interposed sutures involves a complex process, for which molecular and cellular regulatory mechanisms are not well understood. Recent genetic studies have linked various activating mutations in the fibroblast growth factor receptor 2 (FGFR2) gene to a subset of craniosynostosis syndromes, which have in common craniofacial skeletal deformities associated with the premature fusion of cranial sutures. This suggests that FGFR2 may play important roles in skeletal and sutural development. To further develop this notion, the investigators have introduced bone-targeted mFGFR2 transgene constructs, containing an activating mutation (Pro253Arg; an Apert mutation) or a dominant negative mutation, into the mouse germ line and generated several lines of transgenic mice. Initial analyses of these mice revealed that those with an activating mutation manifested some of the typical craniofacial features of craniosynostosis patients. The mice with a dominant negative mutation also displayed a variety of skeletal abnormalities, but they were distinctively different from the craniosynostosis phenotype. Based on pro- mitogenic and anti-apoptotic responses to FGF signaling in bone cells, the investigators hypothesize that an activating FGFR2 mutation promotes proliferation of osteoblasts, while suppressing apoptosis in these cells, resulting in uncontrolled bone formation and, ultimately, suture fusion. In contrast, loss of normal FGFR activities may result in reduced bone cell proliferation with an increased rate of apopotosis, culminating in dystrophic bone and wide-open sutures. To test their hypothesis, the investigators will define the skeletal and suture phenotypes of newly generated transgenic mouse lines (Aim 1), investigate how these mutations alter bone cell functions associated with osteogenesis and suture formation (Aim 2), and finally determine whether the mitogene activated protein (MAP) kinase pathway is involved in some of the altered bone cell functions induced by FGFR2 mutations (Aim 3). Data collected from this pilot study will be used to develop hypotheses to be tested in a larger research project.
| Fakhry, Ali; Ratisoontorn, Chootima; Vedhachalam, Charulatha et al. (2005) Effects of FGF-2/-9 in calvarial bone cell cultures: differentiation stage-dependent mitogenic effect, inverse regulation of BMP-2 and noggin, and enhancement of osteogenic potential. Bone 36:254-66 |
| Mao, Jeremy J; Nah, Hyun-Duck (2004) Growth and development: hereditary and mechanical modulations. Am J Orthod Dentofacial Orthop 125:676-89 |
| Ratisoontorn, Chootima; Fan, Gao-Feng; McEntee, Kerry et al. (2003) Activating (P253R, C278F) and dominant negative mutations of FGFR2: differential effects on calvarial bone cell proliferation, differentiation, and mineralization. Connect Tissue Res 44 Suppl 1:292-7 |
