Morita Jumpei, Nakamura Masataka, Kobayashi Yukiho, Deng Chu-Xia, Funato Noriko, Moriyama Keiji
Maxillofacial Orthognathics, Department of Maxillofacial Reconstruction and Function, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan.
Dev Dyn. 2014 Apr;243(4):560-7. doi: 10.1002/dvdy.24099. Epub 2013 Dec 19.
Apert syndrome (AS) is characterized by craniosynostosis, midfacial hypoplasia, and bony syndactyly. It is an autosomal dominantly inherited disease caused by point mutations (S252W or P253R) in fibroblast growth factor receptor (FGFR) 2. These mutations cause activation of FGFR2 depending on ligand binding. Recently, an AS mouse model, Fgfr2(+/) (S252W) , showed phenotypes similar to those of AS patients. We previously reported that the soluble form of FGFR2(S252W) (sFGFR2IIIc(S252W) ) efficiently inhibits enhanced osteoblastic differentiation caused by FGFR2 activation in AS in vitro, presumably because FGFs binding to FGFRs is interrupted. In this study, we developed Fgfr2(+/) (S252W) (Ap) mice expressing the sFGFR2IIIc(S252W) protein, and we investigated the effects of sFGFR2IIIc(S252W) on AS-like phenotypes.
In Ap mice, the coronal suture (CS) was fused prematurely at P1. In addition, the mice exhibited a widened interfrontal suture (IFS) with ectopic bone and thickened cartilage formation. In Fgfr2(+/) (S252W) sFGFR2IIIc(S252W) (Ap/Sol) mice, the CS was similar to that of wild-type mice. Ap/Sol mice did not show any ectopic bone or cartilage formation in the IFS, but showed a wider IFS than that of the wild-type mice.
sFGFR2IIIc(S252W) may partially prevent craniosynostosis in the Apert mouse model by affecting the CS and IFS in vivo.
Apert综合征（AS）的特征为颅缝早闭、面中部发育不全和骨性并指。它是一种由成纤维细胞生长因子受体（FGFR）2中的点突变（S252W或P253R）引起的常染色体显性遗传病。这些突变导致FGFR2根据配体结合而激活。最近，一种AS小鼠模型Fgfr2(+/)（S252W）表现出与AS患者相似的表型。我们之前报道，FGFR2（S252W）的可溶性形式（sFGFR2IIIc（S252W））在体外可有效抑制AS中由FGFR2激活引起的成骨细胞分化增强，推测是因为成纤维细胞生长因子（FGFs）与FGFRs的结合被阻断。在本研究中，我们构建了表达sFGFR2IIIc（S252W）蛋白的Fgfr2(+/)（S252W）（Ap）小鼠，并研究了sFGFR2IIIc（S252W）对AS样表型的影响。
在Ap小鼠中，冠状缝（CS）在出生后第1天过早融合。此外，小鼠表现出额间缝（IFS）增宽，伴有异位骨和软骨形成增厚。在Fgfr2(+/)（S252W）sFGFR2IIIc（S252W）（Ap/Sol）小鼠中，CS与野生型小鼠相似。Ap/Sol小鼠在IFS中未显示任何异位骨或软骨形成，但IFS比野生型小鼠更宽。
sFGFR2IIIc（S252W）可能通过在体内影响CS和IFS，部分预防Apert小鼠模型中的颅缝早闭。
