Article abstract


Nature Genetics 41, 289 - 298 (2009)
Published online: 15 February 2009 | doi:10.1038/ng.316

FGF9 monomer–dimer equilibrium regulates extracellular matrix affinity and tissue diffusion

Masayo Harada1,2, Hirotaka Murakami3,11, Akihiko Okawa3,11, Noriaki Okimoto4,11, Shuichi Hiraoka1,10,11, Taka Nakahara5,10,11, Ryogo Akasaka6,11, Yo-ichi Shiraishi7,11, Noriyuki Futatsugi4, Yoko Mizutani-Koseki1, Atsushi Kuroiwa7, Mikako Shirouzu6, Shigeyuki Yokoyama6,8, Makoto Taiji4, Sachiko Iseki5, David M Ornitz9 & Haruhiko Koseki1


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.

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  1. RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  2. Department of Immunology and Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
  3. Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
  4. RIKEN Advanced Science Institute, Computational Systems Biology Research Group, 61-1 Ono-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0046, Japan.
  5. Section of Molecular Craniofacial Embryology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
  6. RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  7. Division of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan.
  8. Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
  9. Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
  10. Present addresses: Department of Systems Biomedicine, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan (S.H.) and Section of Developmental and Regenerative Dentistry, School of Life Dentistry at Tokyo, The Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102-8159, Japan (T.N.).
  11. These authors contributed equally to this work.

Correspondence to: Haruhiko Koseki1 e-mail: koseki@rcai.riken.jp



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