FGF9 monomer–dimer equilibrium regulates extracellular matrix affinity and tissue diffusion
Open Access
- 15 February 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 41 (3), 289-298
- https://doi.org/10.1038/ng.316
Abstract
Haruhiko Koseki and colleagues identify a gain-of-function mutation in Fgf9 in mice with elbow knee synostosis. They further show that this mutation prevents homodimerization of Fgf9, allowing increased diffusion of the altered protein through developing tissues. The spontaneous dominant mouse mutant, Elbow knee synostosis (Eks), shows 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 altered 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.Keywords
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