FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion.
FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion.
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DOI：
10.1038/ng.316
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发表时间：
2009-03
期刊：
影响因子：
30.8
通讯作者：
Koseki, Haruhiko
中科院分区：
文献类型：
--
作者：
Harada, Masayo;Murakami, Hirotaka;Okawa, Akihiko;Okimoto, Noriaki;Hiraoka, Shuichi;Nakahara, Taka;Akasaka, Ryogo;Shiraishi, Yo-ichi;Futatsugi, Noriyuki;Mizutani-Koseki, Yoko;Kuroiwa, Atsushi;Shirouzu, Mikako;Yokoyama, Shigeyuki;Taiji, Makoto;Iseki, Sachiko;Ornitz, David M.;Koseki, Haruhiko
自发的显性突变小鼠，肘膝融合(EKS)，表现为肘关节和膝关节融合，以及颅缝过早融合。在这里，我们确定了Fgf9基因中的一个错义突变，它是导致EKS突变的原因。通过对EKS小鼠关节和缝合融合的致病机制的研究，我们确定了在发育中的组织中调节FGF9信号的关键分子机制。我们发现EKS突变阻止了FGF9蛋白的同源二聚化，并且单体FGF9与肝素的亲和力低于二聚体FGF9。这些生化缺陷导致突变的FGF9蛋白(FGF9Eks)在发育中的组织中扩散增加，导致FGF9信号的异位，并抑制关节和缝合的发育。我们提出了一种机制，在发育中的组织中，FGF9信号的范围受到其同质二聚化能力和对细胞外基质硫酸乙酰肝素蛋白多糖的亲和力的限制。
The spontaneous dominant mouse mutant, Elbow-knee-synostosis (Eks), exhibits elbow and knee joint synosotsis, and premature fusion of cranial sutures. Here we identify a missense mutation in the Fgf9 gene that is responsible for the Eks mutation. Through investigation of the pathogenic mechanisms of joint and suture synostosis in Eks mice, we identify a key molecular mechanism that regulates FGF9 signaling in developing tissues. We show that the Eks mutation prevents homodimerization of the FGF9 protein and that monomeric FGF9 binds to heparin with a lower affinity than dimeric FGF9. These biochemical defects result in increased diffusion of the mutant FGF9 protein (FGF9Eks) through developing tissues, leading to ectopic FGF9 signaling and repression of joint and suture development. We propose a mechanism in which the range of FGF9 signaling in developing tissues is limited by its ability to homodimerize and its affinity for extracellular matrix heparan sulfate proteoglycans.
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