Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype

Genes and Development

Volumn 18, Issue 3, 2004, Pages 290-305

  Murakami, Shunichi ^a   Balmes, Gener ^a   McKinney, Sandra ^a   Zhang, Zhaoping ^a   Givol, David ^b   De Crombrugghe, Benoit ^a  

^a UNIVERSITY OF TEXAS   (United States)

^b WEIZMANN INSTITUTE OF SCIENCE   (Israel)

Author keywords

Achondroplasia; Chondrocyte differentiation; FGFR3; MAPK; MEK1; Stat1

Indexed keywords

COLLAGEN TYPE 10; DNA BINDING PROTEIN; FIBROBLAST GROWTH FACTOR RECEPTOR; FIBROBLAST GROWTH FACTOR RECEPTOR 3; GAMMA ACTIVATED FACTOR, 91 KD; GAMMA-ACTIVATED FACTOR, 91-KD; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; STAT1 PROTEIN; TRANSACTIVATOR PROTEIN; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR SOX9; UNCLASSIFIED DRUG;

ACHONDROPLASIA; ANIMAL; ANIMAL CELL; ANIMAL TISSUE; ARTICLE; BONE DEVELOPMENT; BONE GROWTH; CARTILAGE CELL; CELL DIFFERENTIATION; CELL PROLIFERATION; CONTROLLED STUDY; DWARFISM; EMBRYO; ENCHONDRAL OSSIFICATION; FEMALE; GENE MUTATION; GENETICS; GROWTH PLATE; IMMUNOHISTOCHEMISTRY; MALE; METABOLISM; MOUSE; MUTATION; NONHUMAN; NUTRITIONAL DEFICIENCY; OSSIFICATION; PHENOTYPE; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; SKULL BASE; TRANSGENIC MOUSE;

ACHONDROPLASIA; ANIMALS; CELL DIFFERENTIATION; CHONDROCYTES; DNA-BINDING PROTEINS; MAP KINASE KINASE 1; MICE; MICE, TRANSGENIC; MITOGEN-ACTIVATED PROTEIN KINASE KINASES; MUTATION; OSTEOGENESIS; PHENOTYPE; PROTEIN-TYROSINE KINASES; RECEPTOR, FIBROBLAST GROWTH FACTOR, TYPE 3; RECEPTORS, FIBROBLAST GROWTH FACTOR; SIGNAL TRANSDUCTION; STAT1 TRANSCRIPTION FACTOR; TRANS-ACTIVATORS;

ANIMALIA; MUS MUSCULUS;

EID: 1042289662     PISSN: 08909369     EISSN: None     Source Type: Journal    
DOI: 10.1101/gad.1179104     Document Type: Article

References (49)

1. Akiyama, H., Chaboissier, M.C., Martin, J.F., Schedl, A., and de Crombrugghe, B. 2002. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes & Dev. 16: 2813-2828.
2. Bellus, G.A., McIntosh, I., Smith, E.A., Aylsworth, A.S., Kaitila, I., Horton, W.A., Greenhaw, G.A., Hecht, J.T., and Francomano, C.A. 1995. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat. Genet. 10: 357-359.
3. Bi, W., Deng, J.M., Zhang, Z., Behringer, R.R., and de Crombrugghe, B. 1999. Sox9 is required for cartilage formation. Nat. Genet. 22: 85-89.
4. Bi, W., Huang, W., Whitworth, D.J., Deng, J.M., Zhang, Z., Behringer, R.R., and de Crombrugghe, B. 2001. Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc. Natl. Acad. Sci. 98: 6698-6703.
5. Breur, G.J., VanEnkevort, B.A., Farnum, C.E., and Wilsman, N.J. 1991. Linear relationship between the volume of hypertrophic chondrocytes and the rate of longitudinal bone growth in growth plates. J. Orthop. Res. 9: 348-359.
6. Chen, L., Li, C., Qiao, W., Xu, X., and Deng, C. 2001. A Ser(365) → Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. Hum. Mol. Genet. 10: 457-465.
7. Coffin, J.D., Florkiewicz, R.Z., Neumann, J., Mort-Hopkins, T., Dorn II, G.W., Lightfoot, P., German, R., Howles, P.N., Kier, A., O'Toole, B.A., et al. 1995. Abnormal bone growth and selective translational regulation in basic fibroblast growth factor (FGF-2) transgenic mice. Mol. Biol. Cell 6: 1861-1873.
8. Colvin, J.S., Bohne, B.A., Harding, G.W., McEwen, D.G., and Ornitz, D.M. 1996. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat. Genet. 12: 390-397.
9. Coso, O.A., Chiariello, M., Yu, J.C., Teramoto, H., Crespo, P., Xu, N., Miki, T., and Gutkind, J.S. 1995. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 81: 1137-1146.
10. Dailey, L., Laplantine, E., Priore, R., and Basilico, C. 2003. A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation. J. Cell Biol. 161: 1053-1066.
11. Dandolo, L., Stewart, C.L., Mattei, M.G., and Avner, P.R. 1993. Inactivation of an X-linked transgene in murine extraembryonic and adult tissues. Development 118: 641-649.
12. Debiais, F., Lemonnier, J., Hay, E., Delannoy, P., Caverzasio, J., and Marie, P.J. 2001. Fibroblast growth factor-2 (FGF-2) increases N-cadherin expression through protein kinase C and Src-kinase pathways in human calvaria osteoblasts. J. Cell Biochem. 81: 68-81.
13. Delezoide, A.L., Benoist-Lasselin, C., Legeai-Mallet, L., Le Merrer, M., Munnich, A., Vekemans, M., and Bonaventure, J. 1998. Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification. Mech. Dev. 77: 19-30.
14. Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A., and Leder, P. 1996. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84: 911-921.
15. Garofalo, S., Kliger-Spatz, M., Cooke, J.L., Wolstin, O., Lunstrum, G.P., Moshkovitz, S.M., Horton, W.A., and Yayon, A. 1999. Skeletal dysplasia and defective chondrocyte differentiation by targeted overexpression of fibroblast growth factor 9 in transgenic mice. J. Bone Miner. Res. 14: 1909-1915.
16. Iwata, T., Chen, L., Li, C., Ovchinnikov, D.A., Behringer, R.R., Francomano, C.A., and Deng, C.X. 2000. A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos. Hum. Mol. Genet. 9: 1603-1613.
17. Iwata, T., Li, C.L., Deng, C.X., and Francomano, C.A. 2001. Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice. Hum. Mol. Genet. 10: 1255-1264.
18. Kong, M., Wang, C.S., and Donoghue, D.J. 2002. Interaction of fibroblast growth factor receptor 3 and the adapter protein SH2-B. A role in STAT5 activation. J. Biol. Chem. 277: 15962-15970.
19. Lefebvre, V., Garofalo, S., Zhou, G., Metsaranta, M., Vuorio, E., and de Crombrugghe, B. 1994. Characterization of primary cultures of chondrocytes from type II collagen/β-galactosidase transgenic mice. Matrix Biol. 14: 329-335.
20. Lefebvre, V., Huang, W., Harley, V.R., Goodfellow, P.N., and de Crombrugghe, B. 1997. SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro α1(II) collagen gene. Mol. Cell Biol. 17: 2336-2346.
21. Legeai-Mallet, L., Benoist-Lasselin, C., Delezoide, A.L., Munnich, A., and Bonaventure, J. 1998. Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia. J. Biol. Chem. 273: 13007-13014.
22. Lewandoski, M., Wassarman, K.M., and Martin, G.R. 1997. Zp3-Cre, a transgenic mouse line for the activation or inactivation of loxP-flanked target genes specifically in the female germ line. Curr. Biol. 7: 148-151.
23. Li, C., Chen, L., Iwata, T., Kitagawa, M., Fu, X.Y., and Deng, C.X. 1999. A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors. Hum. Mol. Genet. 8: 35-44.
24. Liu, Z., Xu, J., Colvin, J.S., and Omitz, D.M. 2002. Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes & Dev. 16: 859-869.
25. Logan, M., Martin, J.F., Nagy, A., Lobe, C., Olson, E.N., and Tabin, C.J. 2002. Expression of Cre recombinase in the developing mouse limb bud driven by a Prx1 enhancer. Genesis 33: 77-80.
26. CA. Strategies 10: 46-47.
27. Mansour, S.J., Matten, W.T., Hermann, A.S., Candia, J.M., Rong, S., Fukasawa, K., Vande Woude, G.F., and Ahn, N.G. 1994. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265: 966-970.
28. Meraz, M.A., White, J.M., Sheehan, K.C., Bach, E.A., Rodig, S.J., Dighe, A.S., Kaplan, D.H., Riley, J.K., Greenlund, A.C., Campbell, D., et al. 1996. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84: 431-442.
29. Minina, E., Kreschel, C., Naski, M.C., Ornitz, D.M., and Vortkamp, A. 2002. Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev. Cell 3: 439-449.
30. Murakami, S., Kan, M., McKeehan, W.L., and de Crombrugghe, B. 2000. Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. Proc. Natl. Acad. Sci. 97: 1113-1118.
31. Naski, M.C., Colvin, J.S., Coffin, J.D., and Ornitz, D.M. 1998. Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125: 4977-4988.
32. Noonan, K.J., Hunziker, E.B., Nessler, J., and Buckwalter, J.A. 1998. Changes in cell, matrix compartment, and fibrillar collagen volumes between growth-plate zones. J. Orthop. Res. 16: 500-508.
33. Ohbayashi, N., Shibayama, M., Kurotaki, Y., Imanishi, M., Fujimori, T., Itoh, N., and Takada, S. 2002. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes & Dev. 16: 870-879.
34. Peters, K., Ornitz, D., Werner, S., and Williams, L. 1993. Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev. Biol. 155: 423-430.
35. Ronchetti, D., Greco, A., Compasso, S., Colombo, G., Dell'Era, P., Otsuki, T., Lombardi, L., and Neri, A. 2001. Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): Comparative analysis of Y373C, K650E and the novel G384D mutations. Oncogene 20: 3553-3562.
36. Rousseau, F., Bonaventure, J., Legeai-Mallet, L., Pelet, A., Rozet, J.M., Maroteaux, P., Le Merrer, M., and Munnich, A. 1994. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371: 252-254.
37. Rousseau, F., Saugier, P., Le Merrer, M., Munnich, A., Delezoide, A.L., Maroteaux, P., Bonaventure, J., Narcy, F., and Sanak, M. 1995. Stop codon FGFR3 mutations in thanatophoric dwarfism type 1. Nat. Genet. 10: 11-12.
38. Sahni, M., Ambrosetti, D.C., Mansukhani, A., Gertner, R., Levy, D., and Basilico, C. 1999. FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes & Dev. 13: 1361-1366.
39. Sahni, M., Raz, R., Coffin, J.D., Levy, D., and Basilico, C. 2001. STAT1 mediates the increased apoptosis and reduced chondrocyte proliferation in mice overexpressing FGF2. Development 128: 2119-2129.
40. Segev, O., Chumakov, I., Nevo, Z., Givol, D., Madar-Shapiro, L., Sheinin, Y., Weinreb, M., and Yayon, A. 2000. Restrained chondrocyte proliferation and maturation with abnormal growth plate vascularization and ossification in human FGFR-3(G380R) transgenic mice. Hum. Mol. Genet. 9: 249-258.
41. Shiang, R., Thompson, L.M., Zhu, Y.Z., Church, D.M., Fielder, T.J., Bocian, M., Winokur, S.T., and Wasmuth, J.J. 1994. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78: 335-342.
42. Shimoaka, T., Ogasawara, T., Yonamine, A., Chikazu, D., Kawano, H., Nakamura, K., Itoh, N., and Kawaguchi, H. 2002. Regulation of osteoblast, chondrocyte, and osteoclast functions by fibroblast growth factor (FGF)-18 in comparison with FGF-2 and FGF-10. J. Biol. Chem. 277: 7493-7500.
43. Su, W.C., Kitagawa, M., Xue, N., Xie, B., Garofalo, S., Cho, J., Deng, C., Horton, W.A., and Fu, X.Y. 1997. Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature 386: 288-292.
44. Tan, S.S., Williams, E.A., and Tam, P.P. 1993. X-Chromosome inactivation occurs at different times in different tissues of the post-implantation mouse embryo. Nat. Genet. 3: 170-174.
45. Tavormina, P.L., Shiang, R., Thompson, L.M., Zhu, Y.Z., Wilkin, D.J., Lachman, R.S., Wilcox, W.R., Rimoin, D.L., Cohn, D.H., and Wasmuth, J.J. 1995. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat. Genet. 9: 321-328.
46. Vu, T.H., Shipley, J.M., Bergers, G., Berger, J.E., Helms, J.A., Hanahan, D., Shapiro, S.D., Senior, R.M., and Werb, Z. 1998. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93: 411-422.
47. Wang, Y., Spatz, M.K., Kannan, K., Hayk, H., Avivi, A., Gorivodsky, M., Pines, M., Yayon, A., Lonai, P., and Givol, D. 1999. A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. Proc. Natl. Acad. Sci. 96: 4455-4460.
48. Wilsman, N.J., Farnum, C.E., Leiferman, E.M., Fry, M., and Barreto, C. 1996. Differential growth by growth plates as a function of multiple parameters of chondrocytic kinetics. J. Orthop. Res. 14: 927-936.
49. Zhou, G., Garofalo, S., Mukhopadhyay, K., Lefebvre, V., Smith, C.N., Eberspaecher, H., and de Crombrugghe, B. 1995. A 182 bp fragment of the mouse pro α 1(II) collagen gene is sufficient to direct chondrocyte expression in transgenic mice. J. Cell Sci. 108: 3677-3684.