Developmental impairments of craniofacial bone and cartilage in transgenic mice expressing FGF10
Hirotaka Yoshioka,
Kazuko Kagawa,
Tomoko Minamizaki,
Masashi Nakano,
Jane E. Aubin,
Katsuyuki Kozai,
Kazuhiro Tsuga,
Yuji Yoshiko
Affiliations
Hirotaka Yoshioka
Department of Anatomy, School of Medicine, International University of Health and Welfare, Chiba, Japan; Department of Calcified Tissue Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Correspondence to: H. Yoshioka, Department of Anatomy, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba 286-8686, Japan.
Kazuko Kagawa
Department of Calcified Tissue Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Department of Advanced Prosthodontics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
Tomoko Minamizaki
Department of Calcified Tissue Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
Masashi Nakano
Department of Calcified Tissue Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Department of Pediatric Dentistry, Division of Oral Health and Development, Hiroshima University Hospital, Hiroshima, Japan
Jane E. Aubin
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
Katsuyuki Kozai
Department of Pediatric Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
Kazuhiro Tsuga
Department of Advanced Prosthodontics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
Yuji Yoshiko
Department of Calcified Tissue Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Correspondence to: Y. Yoshiko, Department of Calcified Tissue Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima 734-8553, Japan.
Mutations in a common extracellular domain of fibroblast growth factor receptor (FGFR)-2 isoforms (type IIIb and IIIc) cause craniosynostosis syndrome and chondrodysplasia syndrome. FGF10, a major ligand for FGFR2-IIIb and FGFR1-IIIb, is a key participant in the epithelial-mesenchymal interactions required for morphogenetic events. FGF10 also regulates preadipocyte differentiation and early chondrogenesis in vitro, suggesting that FGF10-FGFR signaling may be involved in craniofacial skeletogenesis in vivo. To test this hypothesis, we used a tet-on doxycycline-inducible transgenic mouse model (FGF10 Tg) to overexpress Fgf10 from embryonic day 12.5. Fgf10 expression was 73.3-fold higher in FGF10 Tg than in wild-type mice. FGF10 Tg mice exhibited craniofacial anomalies, such as a short rostrum and mandible, an underdeveloped (cleft) palate, and no tympanic ring. Opposite effects on chondrogenesis in different anatomical regions were seen, e.g., hyperplasia in the nasal septum and hypoplasia in the mandibular condyle. We found an alternative splicing variant of Fgfr2-IIIb with a predicted translation product lacking the transmembrane domain, and suggesting a soluble form of FGFR2-IIIb (sFGFR2-IIIb), differentially expressed in some of the craniofacial bones and cartilages. Thus, excessive FGF10 may perturb signal transduction of the FGF-FGFR, leading to craniofacial skeletal abnormalities in FGF10 Tg mice.
