Chondrocyte Cell Fate Determination in Response to Bone Morphogenetic Protein Signaling

  • Lillian Shum
  • Yuji Hatakeyama
  • Julius Leyton
  • Kazuaki Nonaka


Advances in the understanding of the molecular determinants of skeletal morphogenesis are facilitated by investigating growth and transcription factor regulation of cartilage patterning, chondrocyte cell fate determination, differentiation, and maturation (1). The development of the skeleton is regulated by interacting signaling pathways composed of extrinsic and intrinsic factors. These factors function in synergistic or antagonistic combinations, and some act as rate-limiting elements to regulate cellular development. An understanding of the mechanisms by which these multiple and diverse pathways interact as networks contributes to early gene- or biomarker-based detection and diagnosis of diseases and disorders that affect cartilage, such as osteoarthritis. Furthermore, the knowledge base provides the necessary foundation for prevention and treatment strategies, such as gene therapy, tissue engineering, and other orthopedic applications.


Bone Morphogenetic Protein Neural Crest Neural Crest Cell Apical Ectodermal Ridge Target Disruption 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Shum, L. and Nuckolls, G. (2002) The life cycle of chondrocytes in the developing skeleton. Arthritis Res. 4, 14994–15106.CrossRefGoogle Scholar
  2. 2.
    Lee, S., Christakos, S., and Small, M. B. (1993) Apoptosis and signal transduction: clues to a molecular mechanism. Curr. Opin. Cell. Biol. 5, 286–291.PubMedCrossRefGoogle Scholar
  3. 3.
    Chen, Y. and Zhao, X. (1998) Shaping limbs by apoptosis. J. Exp. Zool. 282, 691–702.PubMedCrossRefGoogle Scholar
  4. 4.
    Graham, A., Koentges, G., and Lumsden, A. (1996) Neural crest apoptosis and the establishment of craniofacial pattern: an honorable death. Mol. Cell Neurosci. 8, 76–83.CrossRefGoogle Scholar
  5. 5.
    Graham, A., Francis-West, P., Brickell, P., and Lumsden, A. (1994) The signalling molecule BMP4 mediates apoptosis in the rhombencephalic neural crest. Nature 372, 684–686.PubMedCrossRefGoogle Scholar
  6. 6.
    Tang, M. K., Leung, A. K., Kwong, W. H., Chow, P. H., Chan, J. Y., Ngo-Muller, V., Li, M., and Lee, K. K. (2000) Bmp-4 requires the presence of the digits to initiate programmed cell death in limb interdigital tissues. Dey. Biol. 218, 89–98.CrossRefGoogle Scholar
  7. 7.
    Ros, M. A., Piedra, M. E., Fallon, J. F., and Hurle, J. M. (1997) Morphogenetic potential of the chick leg interdigital mesoderm when diverted from the cell death program. Dey. Dyn. 208, 406–419.CrossRefGoogle Scholar
  8. 8.
    de Crombrugghe, B., Lefebvre, V., Behringer, R. R., Bi, W., Murakami, S., and Huang, W. (2000) Transcriptional mechanisms of chondrocyte differentiation. Matrix Biol. 19, 389–394.PubMedCrossRefGoogle Scholar
  9. 9.
    Wagner, T., Wirth, J., Meyer, J., Zabel, B., Held, M., Zimmer, J., et al. (1994) Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-rclatcd gcnc SOX9. Cell 79, 1111–1120.PubMedCrossRefGoogle Scholar
  10. 10.
    Foster, J. W., Dominguez-Steglich, M. A., Guioli, S., Kowk, G., Weller, P. A., Stevanovic, M., et al. (1994) Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 372. 525–530.PubMedCrossRefGoogle Scholar
  11. 11.
    Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L., and Karsenty, G. (1997) Osf2/Cbfa 1 : a transcriptional activator of osteoblast differentiation. Cell 89, 747–754.PubMedCrossRefGoogle Scholar
  12. 12.
    Rodriguez-Esteban, C., Tsukui, T., Yonei, S., Magallon, J., Tamura, K., and Izpisua Belmonte, J. C. (1999) The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity. Nature 398, 814–818.PubMedCrossRefGoogle Scholar
  13. 13.
    Takahashi, K., Nuckolls, G. H., Tanaka, O., Semba, I., Takahashi, I., Dashner, R., Shum, L., and Slavkin, H. C. (1998) Adenovirus-mediated ectopic expression of Msx2 in even-numbered rhombomeres induces apoptotic elimination of cranial neural crest cells in ovo. Development 125, 1627–1635.PubMedGoogle Scholar
  14. 14.
    Dunn, N. R., Winnier, G. E., Hargett, L. K., Schrick, J. J., Fogo, A. B., and Hogan, B. L. (1997) Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in G1i3 and A1x4. Dev. Biol. 188, 235–247.PubMedCrossRefGoogle Scholar
  15. 15.
    Zehentner, B. K., Haussmann, A., and Burtscher, H. (2002) The bone morphogenetic protein antagonist Noggin is regulated by Sox9 during endochondral differentiation. Dev. Growth Differ. 44. 1–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Urist, M. R. (1965) Bone: formation by autoinduction. Science 150, 893–899.PubMedCrossRefGoogle Scholar
  17. 17.
    Ducy, P. and Karsenty, G. (2000) The yfamily of bone morphogenetic proteins. Kidney Int. 57, 2207–2214.PubMedCrossRefGoogle Scholar
  18. 18.
    Wozney, J. M. (1998) The bone morphogenetic protein family: multifunctional cellular regulators in the embryo and adult. Eur. J. Oral. Sci. 106, 160–166.PubMedGoogle Scholar
  19. 19.
    Graff, J. M. (1997) Embryonic patterning: to BMP or not to BMP, that is the question. Cell 89, 171–174.PubMedCrossRefGoogle Scholar
  20. 20.
    Hogan, B. L. (1996) Bone morphogenetic proteins in development. Curr. Opin. Genet. Dev. 6,432–438.PubMedCrossRefGoogle Scholar
  21. 21.
    Mehler, M. F., Mabie, P. C., Zhu, G., Gokhan, S., and Kessler, J. A. (2000) Developmental changes in progenitor cell responsiveness to bone morphogenetic proteins differentially modulate progressive CNS lineage fate. Dev. Neurosci. 22, 74–85.PubMedCrossRefGoogle Scholar
  22. 22.
    Reddi, A. H. (2001) Interplay between bone morphogenetic proteins and cognate binding proteins in bone and cartilage development: noggin, chordin and DAN. Arthritis Res. 3, 1–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Balemans, W. and Hul, W. V. (2002) Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Dev. Biol. 250, 231–250.PubMedCrossRefGoogle Scholar
  24. 24.
    Hoffmann, A. and Gross, G. (2001) BMP signaling pathways in cartilage and bone formation. Crit. Rev. Eukaryot. Gene Exp. 11, 23–45.Google Scholar
  25. 25.
    Kingsley, D. M. (2001) Genetic control of bone and joint formation. Novartis Found. Sympos. 232, 213–222; discussion 222–234, 272–282.CrossRefGoogle Scholar
  26. 26.
    Yoon, S. T. and Boden, S. D. (2002) Osteoinductive molecules in orthopaedics: basic science and preclinical studies. Clin. Orthop. Feb, 33–43.Google Scholar
  27. 27.
    King, G. N. (2001) The importance of drug delivery to optimize the effects of bone morphogenetic proteins during periodontal regeneration. Curr. Pharm. Biotechnol. 2, 131–142.PubMedCrossRefGoogle Scholar
  28. 28.
    Li, R. H. and Wozney, J. M. (2001) Delivering on the promise of bone morphogenetic proteins. Trends Biotechnol. 19. 255–265PubMedCrossRefGoogle Scholar
  29. 29.
    Wikesjo, U. M., Sorensen, R. G., and Wozney, J. M. (2001) Augmentation of alveolar bone and dental implant osseointegration: clinical implications of studies with rhBMP-2. J. Bone Joint. Surg. Am. 83-A Suppl 1, S136–S145.PubMedGoogle Scholar
  30. 30.
    Reddi, A. H. (2001) Bone morphogenetic proteins: from basic science to clinical applications. J. Bone Joint. Surg. Am. 83-A SuDpl 1. S1–S6.PubMedGoogle Scholar
  31. 31.
    Mathews, L. S. and Vale, W. W. (1991) Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell 65, 973–982.PubMedCrossRefGoogle Scholar
  32. 32.
    Miyazono, K., Kusanagi, K., and Inoue, H. (2001) Divergence and convergence of TGF-beta/BMP signaling. J. Cell. Physiol. 187, 265–276.PubMedCrossRefGoogle Scholar
  33. 33.
    Kawabata, M., Imamura, T., and Miyazono, K. (1998) Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev. 9, 49–61.PubMedCrossRefGoogle Scholar
  34. 34.
    Nohe, A., Hassel, S., Ehrlich, M., Neubauer, F., Sebald, W., Henis, Y. I., and Knaus, P. (2002) The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J. Biol. Chem. 277. 5330–5338.PubMedCrossRefGoogle Scholar
  35. 35.
    Knaus, P. and Sebald, W. (2001) Cooperativity of binding epitopes and receptor chains in the BMP/TGFbeta superfamily. J. Biol. Chem. 382, 1189–1195.Google Scholar
  36. 36.
    Sandell, L. J. and Adler, P. (1999) Developmental patterns of cartilage. Front. Biosci. 4, D731–D742.PubMedCrossRefGoogle Scholar
  37. 37.
    Zou, H., Wieser, R., Massague, J., and Niswander, L. (1997) Distinct roles of type I bone morphogenetic protein receptors in the formation and differentiation of cartilage. Genes Dev. 11, 2191–2203.PubMedCrossRefGoogle Scholar
  38. 38.
    Cheifetz, S. (1999) BMP receptors in limb and tooth formation. Crit. Rev. Oral Biol. Med. 10, 182–198.PubMedCrossRefGoogle Scholar
  39. 39.
    Yi, S. E., Daluiski, A., Pederson, R., Rosen, V., and Lyons, K. M. (2000) The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limB. Development 127, 621–630.PubMedGoogle Scholar
  40. 40.
    Baur, S. T., Mai, J. J., and Dymecki, S. M. (2000) Combinatorial signaling through BMP receptor IB and GDF5: shaping of the distal mouse limb and the genetics of distal limb diversity. Development 127, 605–619.PubMedGoogle Scholar
  41. 41.
    Akiyama, S., Katagiri, T., Namiki, M., Yamaji, N., Yamamoto, N., Miyama, K., et al. (1997) Constitutively active BMP type I receptors transduce BMP-2 signals without the ligand in C2C12 myoblasts. Exp. Cell Res. 235, 362–369.PubMedCrossRefGoogle Scholar
  42. 42.
    Kawakami, Y., Ishikawa, T., Shimabara, M., Tanda, N., Enomoto-Iwamoto, M., Iwamoto, M., et al. (1996) BMP signaling dduiring hone nattern determination in the developing limB. Development 122, 3557–3566.PubMedGoogle Scholar
  43. 43.
    Shukunami, C., Akiyama, H., Nakamura, T., and Hiraki, Y. (2000) Requirement of autocrine signaling by bone morphogenetic protein-4 for chondrogenic differentiation of ATDC5 cells. FEBS Lett. 469, 83–87.PubMedCrossRefGoogle Scholar
  44. 44.
    Moustakas, A., Souchelnytskyi, S., and Heldin, C. H. (2001) Smad regulation in TGF-beta signal transduction. J. Cell. Sci. 114, 4359–4369.PubMedGoogle Scholar
  45. 45.
    Shi, Y. (2001) Structural insights on Smad function in TGFbeta signaling. Bioessays 23,223–232.PubMedCrossRefGoogle Scholar
  46. 46.
    Nonaka, K., Shum, L., Takahashi, I., Takahashi, K., Ikura, T., Dashner, R., Nuckolls, G. H., and Slavkin, H. C. (1999) Convergence of the BMP and EGF signaling pathways on Smad1 in the regulation of chondrogenesis. Int. J. Dev. Biol. 43. 795–807.PubMedGoogle Scholar
  47. 47.
    Ju, W., Hoffmann, A., Verschueren, K., Tylzanowski, P., Kaps, C., Gross, G., and Huylebroeck, D. (2000) The bone morphogenetic protein 2 signaling mediator Smad1 participates predominantly in osteogenic and not in chondrogenic differentiation in mesenchvmal progenitors C3H10T1/2. J. Bone Miner. Res. 15, 1889–1899.PubMedCrossRefGoogle Scholar
  48. 48.
    Fujii, M., Takeda, K., Imamura, T., Aoki, H., Sampath, T. K., Enomoto, S., et al. (1999) Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. Mol. Biol. Cell. 10, 3801–3813.PubMedGoogle Scholar
  49. 49.
    Nishimura, R., Kato, Y., Chen, D., Harris, S. E., Mundy, G. R., and Yoneda, T. (1998) Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12. J. Biol. Chem. 273, 1872–1879.PubMedCrossRefGoogle Scholar
  50. 50.
    Weinstein, M., Yang, X., and Deng, C. (2000) Functions of mammalian Smad genes as revealed by targeted gene disruption in mice. Cytokine Growth Factor Rev. 11, 49–58.PubMedCrossRefGoogle Scholar
  51. 51.
    Yang, X., Chen, L., Xu, X., Li, C., Huang, C., and Deng, C. X. (2001) TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J. Cell. Biol. 153, 35–46.PubMedCrossRefGoogle Scholar
  52. 52.
    Hayashi, H., Abdollah, S., Qiu, Y., Cai, J., Xu, Y. Y., Grinnell, B. W., et al. (1997) The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell 89, 1165–1173.PubMedCrossRefGoogle Scholar
  53. 53.
    Nakao, A., Afrakhte, M., Moren, A., Nakayama, T., Christian, J. L., Heuchel, R., et al. (1997) Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 389, 631–635.PubMedCrossRefGoogle Scholar
  54. 54.
    Imamura, T., Takase, M., Nishihara, A., Oeda, E., Hanai, J., Kawabata, M., and Miyazono, K. (1997) Smad6 inhibits signalling by the TGF-beta superfamily. Nature 389, 622–626.PubMedCrossRefGoogle Scholar
  55. 55.
    Ishida, W., Hamamoto, T., Kusanagi, K., Yagi, K., Kawabata, M., Takehara, K., et al. (2000) Smad6 is a Smad1/5-induced smad inhibitor. Characterization of bone morphogenetic protein-responsive element in the mouse Smad6 promoter. J. Biol. Chem. 275. 6075–6079.PubMedCrossRefGoogle Scholar
  56. 56.
    Hata, A., Lagna, G., Massague, J., and Hemmati-Brivanlou, A. (1998) Smad6 inhibits BMP/Smadl signaling by specifically comneting with the Smad4 tumor suppressor. Genes Dev. 12, 186–197.PubMedCrossRefGoogle Scholar
  57. 57.
    Valcourt, U., Gouttenoire, J., Moustakas, A., Herbage, D., and Mallein-Gerin, F. (2002) Functions of transforming growth factor-beta family type i receptors and smad proteins in the hypertrophic maturation and osteoblastic differentiation of chondrocytes. J. Biol. Chem. 277, 33545–33558.PubMedCrossRefGoogle Scholar
  58. 58.
    Ito, Y., Bringas, P. Jr., Mogharei, A., Zhao, J., Deng, C., and Chai, Y. (2002) Receptor-regulated and inhibitory Smads are critical in regulating transforming growth factorbeta-mediated Meckel’s cartilage development. Dev. Dyn. 224, 69–78PubMedCrossRefGoogle Scholar
  59. 59.
    Attisano, L. and Wrana, J. L. (2000) Smads as transcriptional co-modulators. Curr. Opin. Cell. Biol. 12, 235–243.PubMedCrossRefGoogle Scholar
  60. 60.
    Schutte, M. (1999) DPC4/SMAD4 gene alterations in human cancer, and their functional implications. Ann. Oncol. 10, 56–59.PubMedCrossRefGoogle Scholar
  61. 61.
    Letamendia, A., Labbe, E., and Attisano, L. (2001) Transcriptional regulation by Smads: crosstalk between the TGF-beta and Wnt pathways. J. Bone Joint. Surg. Am. 83-A Suppl 1, S31–S39.PubMedGoogle Scholar
  62. 62.
    Fischer, L., Boland, G., and Tuan, R. S. (2002) Wnt-3A enhances bone morphogenetic protein-2-mediated chondrogenesis of murine C3H10T1/2 mesenchymal cells. J. Biol. Chem. 277, 30870–20878.PubMedCrossRefGoogle Scholar
  63. 63.
    Mulder, KM. (2000) Role of Ras and Mapks in TGFbeta signaling. Cytokine Growth Factor Rev. 11, 23–35.Google Scholar
  64. 64.
    Williams, J. G. (2000) STAT signalling in cell proliferation and in development. Curr. Opin. Genet. Dev. 10, 503–507.PubMedCrossRefGoogle Scholar
  65. 65.
    Zhang, Y. and Derynck, R. (1999) Regulation of Smad signalling by protein associations and signalling crosstalk. Trends Cell Biol. 9, 274–279.PubMedCrossRefGoogle Scholar
  66. 66.
    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. USA 97.1113–1118.PubMedCrossRefGoogle Scholar
  67. 67.
    Le Douarin, N. M. (1982) The Neural Crest. Cambridge University Press, Cambridge, UK.Google Scholar
  68. 68.
    Le Lievre, C. S. and Le Douarin, N. M. (1975) Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos. J. Embryo’. Exp. Morphol. 34, 125–154.Google Scholar
  69. 69.
    Noden, D. M. (1983) The role of the neural crest in patterning of avian cranial skeletal, connective, and muscle tissues. Dev. Biol. 96, 144–165.PubMedCrossRefGoogle Scholar
  70. 70.
    Tan, S. S. and Morriss-Kay, G. (1985) The development and distribution of the cranial neural crest in the rat embryo. Cell Tissue Res. 240, 403–416.PubMedCrossRefGoogle Scholar
  71. 71.
    Baker, C. V., Bronner-Fraser, M., Le Douarin, N. M., and Teillet, M. A. (1997) Early- and late-migrating cranial neural crest cell populations have equivalent developmental potential in vivo. Development 124, 3077–3087.PubMedGoogle Scholar
  72. 72.
    Baroffio, A., Dupin, E., and Le Douarin, N. M. (1991) Common precursors for neural and mesectodermal derivatives in the cephalic neural crest. Development 112, 301–305.PubMedGoogle Scholar
  73. 73.
    Epperlein, H., Meulemans, D., Bronner-Fraser, M., Steinbeisser, H., and Selleck, M. A. (2000) Analysis of cranial neural crest migratory pathways in axolotl using cell markers and transplantation. Development 127, 2751–2761.PubMedGoogle Scholar
  74. 74.
    McGonnell, T. M. and Graham, A. (2002) Trunk neural crect hac ckeletnggenic nntential Curr Biol. 12, 767–771PubMedCrossRefGoogle Scholar
  75. 75.
    Morriss-Kay, G., Ruberte, E., and Fukiishi, Y. (1993) Mammalian neural crest and neural crest derivatives. Anat. Anz. 175, 501–507.CrossRefGoogle Scholar
  76. 76.
    Chareonvit, S., Osumi-Yamashita, N., Ikeda, M., and Eto, K. (1997) Murine forebrain and midbrain crest cells generate different characteristic derivatives in vitro. Dev. Growth Differ. 39, 493–503.PubMedCrossRefGoogle Scholar
  77. 77.
    Osumi-Yamashita, N., Ninomiya, Y., Doi, H., and Eto, K. (1994) The contribution of both forebrain and midbrain crest cells to the mesenchvme in the frontonasal mass of mouse embryos. Dev. Biol. 164. 409–419.PubMedCrossRefGoogle Scholar
  78. 78.
    Wedden, S. E., Ralphs, J. R., and Tickle, C. (1988) Pattern formation in the facial primordia. Development 103, 31–40.PubMedGoogle Scholar
  79. 79.
    Morriss-Kay, G. and Tucket, F. (1991) Early events in mammalian craniofacial morphogenesis. J. Craniofac. Genet. Dev. Biol. 11, 181–191.PubMedGoogle Scholar
  80. 80.
    Serbedzija, G. N., Bronner-Fraser, M., and Fraser, S. E. (1992) Vital dye analysis of cranial neural crest cell migration in the mouse embryo. Development 116, 297–307.PubMedGoogle Scholar
  81. 81.
    Lumsden, A. and Keynes, R. (1989) Segmental patterns of neuronal development in the chick hindbrain. Nature 337, 424–428.PubMedCrossRefGoogle Scholar
  82. 82.
    Trainor, P. A., Sobieszczuk, D., Wilkinson, D., and Krumlauf, R. (2002) Signalling between the hindbrain and paraxial tissues dictates neural crest migration pathways. Development 129, 433–442.PubMedGoogle Scholar
  83. 83.
    Hunt, P., Wilkinson, D., and Krumlauf, R. (1991) Patterning the vertebrate head: murine Hox 2 genes mark distinct subpopulations of premigratory and migrating cranial neural crest. Development 112, 43–50.PubMedGoogle Scholar
  84. 84.
    Vaglia, J. L. and Hall, B. K. (1999) Regulation of neural crest cell populations: occurrence, distribution and underlying mechanisms. Int. J. Dev. Biol. 43. 95–110.PubMedGoogle Scholar
  85. 85.
    Trainor, P. A. and Krumlauf, R. (2000) Patterning the cranial neural crest: hindbrain segmentation and Hox gene plasticity. Nat. Rev. Neurosci. 1, 116–124.PubMedCrossRefGoogle Scholar
  86. 86.
    Grapin-Botton, A., Bonnin, M. A., and Le Douarin, N. M. (1997) Hox gene induction in the neural tube depends on three parameters: competence, signal supply and paralogue group. Development 124, 849–859.PubMedGoogle Scholar
  87. 87.
    Schilling, T. F., Prince, V., and Ingham, P. W. (2001) Plasticity in zebrafish hox expression in the hindbrain and cranial neural crest. Dev. Biol. 231, 201–216.PubMedCrossRefGoogle Scholar
  88. 88.
    Trainor, P. and Krumlauf, R. (2000) Plasticity in mouse neural crest cells reveals a new patterning role for cranial mesoderm. Nat. Cell Biol. 2, 96–102.PubMedCrossRefGoogle Scholar
  89. 89.
    Trainor, P. A., Ariza-McNaughton, L., and Krumlauf, R. (2002) Role of the isthmus and FGFs in resolving the paradox of neural crest plasticity and prepatterning. Science 295, 1288–1291.PubMedCrossRefGoogle Scholar
  90. 90.
    Couly, G., Creuzet, S., Bennaceur, S., Vincent, C., and Le Douarin, N. M. (2002) Interactions between Hox-negative cephalic neural crest cells and the foregut endoderm in patterning the facial skeleton in the vertebrate head. Development 129, 1061–1073.PubMedGoogle Scholar
  91. 91.
    Jeffs, P., Jaques, K., and Osmond, M. (1992) Cell death in cranial neural crest development. Anat. Embryol. (Berl.) 185, 583–588.Google Scholar
  92. 92.
    Lumsden, A., Sprawson, N., and Graham, A. (1991) Segmental origin and migration of neural crest cells in the hindbrain region of the chick embryo. Development 113, 1281–1291.PubMedGoogle Scholar
  93. 93.
    Graham, A., Heyman, I., and Lumsden, A. (1993) Even-numbered rhombomeres control the apoptotic elimination of neural crest cells from odd-numbered rhombomeres in the chick hindbrain. Development 119, 233–245.PubMedGoogle Scholar
  94. 94.
    Sechrist, J., Scherson, T., and Bronner-Fraser, M. (1994) Rhombomere rotation reveals that multiple mechanisms contribute to the segmental pattern of hindbrain neural crest migration. Development 120, 1777–1790.PubMedGoogle Scholar
  95. 95.
    Sechrist, J., Serbedzija, G. N., Scherson, T., Fraser, S. E., and Bronner-Fraser, M. (1993) Segmental migration of the hindbrain neural crest does not arise from its segmental generation. Development 118, 691–703.PubMedGoogle Scholar
  96. 96.
    Birgbauer, E., Sechrist, J., Bronner-Fraser, M., and Fraser, S. (1995) Rhombomeric origin and rostrocaudal reassortment of neural crest cells revealed by intravital microscopy. Development 121, 935–945.PubMedGoogle Scholar
  97. 97.
    Kontges, G. and Lumsden, A. (1996) Rhombencephalic neural crest segmentation is preserved throughout craniofacial ontogeny. Development 122, 3229–3242.PubMedGoogle Scholar
  98. 98.
    Farlie, P. G., Kerr, R., Thomas, P., Symes, T., Minichiello, J., Hearn, C. J., et al. (1999) A paraxial exclusion zone creates patterned cranial neural crest cell outgrowth adjacent to rhombomeres 3 and 5. Dev. Biol. 213, 70–84.PubMedCrossRefGoogle Scholar
  99. 99.
    Graham, A. and Lumsden, A. (1996) Patterning the cranial neural crest. Biochem. Soc. Sympos. 62, 77–83.Google Scholar
  100. 100.
    Smith, A. and Graham, A. (2001) Restricting Bmp-4 mediated apoptosis in hindbrain neural crest. Dev. Dyn. 220, 276–283.PubMedCrossRefGoogle Scholar
  101. 101.
    Ellies, D. L., Church, V., Francis-West, P., and Lumsden, A. (2000) The WNT antagonist cSFRP2 modulates programmed cell death in the developing hindbrain. Development 127, 5285–5295.PubMedGoogle Scholar
  102. 102.
    Garcia-Castro, M. I., Marcelle, C., and Bronner-Fraser, M. (2002) Ectodermal Wnt Function As a Neural Crest Inducer. Science 297, 848–851.PubMedGoogle Scholar
  103. 103.
    Lallier, T. E. (1991) Cell lineage and cell migration in the neural crest. Ann. NY Acad. Sci. 615, 158–171.PubMedCrossRefGoogle Scholar
  104. 104.
    Spokony, R. F., Aoki, Y., Saint-Germain, N., Magner-Fink, E., and Saint-Jeannet, J. P. (2002) The transcription factor Sox9 is required for cranial neural crest development in Xenopus. Development 129, 421–432.PubMedGoogle Scholar
  105. 105.
    Takahashi, K., Nuckolls, G. H., Takahashi, I., Nonaka, K., Nagata, M., Ikura, T., Slavkin, H. C., and Shum, L. (2001) Msx2 is a repressor of chondrogenic differentiation in migratory cranial neural crest cells. Dev. Dyn. 222, 252–262.PubMedCrossRefGoogle Scholar
  106. 106.
    Le Lievre, C. S. (1978) Participation of neural crest-derived cells in the genesis of the skull in birds. J. Embryol. Exp. Morphol. 47, 17–37.PubMedGoogle Scholar
  107. 107.
    Chai, Y., Jiang, X., Ito, Y., Bringas, P. Jr., Han, J., Rowitch, D. H., et al. (2000) Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development 127, 1671–1679.PubMedGoogle Scholar
  108. 108.
    Hall, B. K. (1980) Tissue interactions and the initiation of osteogenesis and chondrogenesis in the neural crestderived mandibular skeleton of the embryonic mouse as seen in isolated murine tissues and in recombinations of murine and avian tissues. J. Embryol. Exp. Morphol. 58, 251–264.PubMedGoogle Scholar
  109. 109.
    Tyler, M. S. and Hall, B. K. (1977) Epithelial influences on skeletogenesis in the mandible of the embryonic chick. Anat. Rec. 188, 229–239.PubMedCrossRefGoogle Scholar
  110. 110.
    Coffin-Collins, P. A. and Hall, B. K. (1989) Chondrogenesis of mandibular mesenchyme from the embryonic chick is inhibited by mandibular enithelium and by epidermal growth factor. Int. J. Dev. Biol. 33, 297–311.PubMedGoogle Scholar
  111. 111.
    Hall, B. K. and Coffin-Collins, P. A. (1990) Reciprocal interactions between epithelium, mesenchyme, and epidermal growth factor (EGF) in the regulation of mandibular mitotic activity in the embryonic chick. J. Craniofac. Genet. Dev. Biol. 10, 241–261.PubMedGoogle Scholar
  112. 112.
    Kollar, E. J. and Mina, M. (1991) Role of the early epithelium in the patterning of the teeth and Meckel’s cartilage. J. Craniofac. Genet. Dev. Biol. 11, 223–228.PubMedGoogle Scholar
  113. 113.
    Mina, M., Upholt, W. B., and Kollar, E. J. (1994) Enhancement of avian mandibular chondrogenesis in vitro in the absence of epithelium. Arch. Oral Biol. 39, 551–562.PubMedCrossRefGoogle Scholar
  114. 114.
    Kronmiller, J. E., Upholt, W. B., and Kollar, E. J. (1991) Expression of epidermal growth factor mRNA in the developing mouse mandibular process. Arch. Oral. Biol. 36, 405–410.PubMedCrossRefGoogle Scholar
  115. 115.
    Shum, L., Sakakura, Y., Bringas, P. Jr., Luo, W., Snead, M. L., Mayo, M., et al. (1993) EGF abrogation-induced fusilli-form dysmorphogenesis of Meckel’s cartilage during embryonic mouse mandibular morphogenesis in vitro. Development 118, 903–917.PubMedGoogle Scholar
  116. 116.
    Miettinen, P. J., Chin, J. R., Shum, L., Slavkin, H. C., Shuler, C. F., Derynck, R. et al. (1999) Epidermal growth factor receptor function is necessary for normal craniofacial development and palate closure. Nat. Genet. 22, 69–73.PubMedCrossRefGoogle Scholar
  117. 117.
    Chin, J. R. and Werb, Z. (1997) Matrix metalloproteinases regulate morphogenesis, migration and remodeling of epithelium. tongue skeletal muscle and cartilage in the mandibular arch. Development 124, 1519–1530.PubMedGoogle Scholar
  118. 118.
    Mina, M., Gluhak, J., Upholt, W. B., Kollar, E. J., and Rogers, B. (1995) Experimental analysis of Msx-1 and Msx2 gene expression during chick mandibular morphogenesis. Dey. Dyn. 202, 195–214.CrossRefGoogle Scholar
  119. 119.
    Mina, M., Gluhak, J., and Rodgers, B. (1996) Downregulation of Msx-2 expression results in chondrogenesis in the medial region of the avian mandible. Connect. Tissue Res. 35, 79–84.PubMedCrossRefGoogle Scholar
  120. 120.
    Semba, I., Nonaka, K., Takahashi, I., Takahashi, K., Dashner, R., Shum, L., et al. (2000) Positionally-dependent chondrogenesis induced by BMP4 is co-regulated by Sox9 and Msx2. Dev. Dyn. 217, 401–414.PubMedCrossRefGoogle Scholar
  121. 121.
    Ekanayake, S. and Hall, B. K. (1997) The in vivo and in vitro effects of bone morphogenetic protein-2 on the development of the chick mandible. Int. J. Dev. Biol. 41, 67–81.PubMedGoogle Scholar
  122. 122.
    Barlow, A. J. and Francis-West, P. H. (1997) Ectopic application of recombinant BMP-2 and BMP-4 can change patterning of developing chick facial primordia. Development 124, 391–398.PubMedGoogle Scholar
  123. 123.
    Capdevila, J. and Izpisua Belmonte, J. C. (2001) Patterning mechanisms controlling vertebrate limb development. Annu. Rev. Cell Dev. Biol. 17, 87–132.PubMedCrossRefGoogle Scholar
  124. 124.
    Ng, J. K., Tamura, K., Buscher, D., and Izpisua-Belmonte, J. C. (1999) Molecular and cellular basis of pattern formation during vertebrate limb development. Curr. Top Dev. Biol. 41, 37–66.PubMedCrossRefGoogle Scholar
  125. 125.
    Lewandoski, M., Sun, X., and Martin, G. R. (2000) Fgf8 signalling from the AER is essential for normal limb development. Nat. Genet. 26, 460–463.PubMedCrossRefGoogle Scholar
  126. 126.
    Sun, X., Lewandoski, M., Meyers, E. N., Liu, Y. H., Maxson, R. E. Jr., and Martin, G. R. (2000) Conditional inactivation cif Fgf4 reveals complexitv of signalling during limb bud development. Nat. Genet. 25, 83–86.PubMedCrossRefGoogle Scholar
  127. 127.
    Martin, G. R. (1998) The roles of FGFs in the early development of vertebrate limbs. Genes Dev. 12, 1571–1586.PubMedCrossRefGoogle Scholar
  128. 128.
    Sun, X., Mariani, F. V., and Martin, G. R. (2002) Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature 418, 501–508.PubMedCrossRefGoogle Scholar
  129. 129.
    Xu, X., Weinstein, M., Li, C., and Deng, C. (1999) Fibroblast growth factor receptors (FGFRs) and their roles in limb ddeveloppment. Cell Tissue Res. 296. 33–43.PubMedCrossRefGoogle Scholar
  130. 130.
    Niswander, L. (1996) Growth factor interactions in limb development. Ann. NY Acad. Sci. 785, 23–26.PubMedCrossRefGoogle Scholar
  131. 131.
    Wolpert, L. (1969) Positional information and the spatial pattern of cellular differentiation. J. Theor. Biol. 25, 1–47.PubMedCrossRefGoogle Scholar
  132. 132.
    Dudley, A. T., Ros, M. A., and Tabin, C. J. (2002) A re-examination of proximodistal patterning during vertebrate limb development. Nature 418, 539–544.PubMedCrossRefGoogle Scholar
  133. 133.
    Johnson, R. L., Riddle, R. D., Laufer, E., and Tabin, C. (1994) Sonic hedgehog: a key mediator of anterior-posterior patterning of the limb and dorso-ventral patterning of axial embryonic structures. Biochem. Soc. Trans. 22, 569–574.PubMedGoogle Scholar
  134. 134.
    Tickle, C. and Eichele, G. (1994) Vertebrate limb development. Annu. Rev. Cell. Biol. 10, 121–152.PubMedCrossRefGoogle Scholar
  135. 135.
    Riddle, R. D., Johnson, R. L., Laufer, E., and Tabin, C. (1993) Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75, 1401–1416.PubMedCrossRefGoogle Scholar
  136. 136.
    Duboule, D. (1992) The vertebrate limb: a model system to study the Hox/HOM gene network during development and evolution. Bioessays 14, 375–384.PubMedCrossRefGoogle Scholar
  137. 137.
    Pearse, R. V. II and Tabin, C. J. (1998) The molecular ZPA. J. Exp. Zool. 282, 677–690.PubMedCrossRefGoogle Scholar
  138. 138.
    Chen, H. and Johnson, R. L. (1999) Dorsoventral patterning of the vertebrate limb: a process governed by multiple events. Cell Tissue Res. 296, 67–73.PubMedCrossRefGoogle Scholar
  139. 139.
    Zeller, R. and Duboule, D. (1997) Dorso-ventral limb polarity and origin of the ridge: on the fringe of independence? Bioessavs 19, 541–546.CrossRefGoogle Scholar
  140. 140.
    Yokouchi, Y., Sasaki, H., and Kuroiwa, A. (1991) Homeobox gene expression correlated with the bifurcation process of limb cartilage development. Nature 353. 443–445.PubMedCrossRefGoogle Scholar
  141. 141.
    Dolle P., Izpisua-Belmonte, J. C., Brown, J., Tickle, C., and Duboule, D. (1993) Hox genes and the morphogenesis of the vertebrate limB. Prog. Clin. Biol. Res. 383A, 11–20.PubMedGoogle Scholar
  142. 142.
    Merino, R., Ganan, Y., Macias, D., Rodriguez-Leon, J., and Hurle, J. M. (1999) Bone morphogenetic proteins regulate interdigital cell death in the avian embryo. Ann. NY Acad. Sci. 887, 120–132.PubMedCrossRefGoogle Scholar
  143. 143.
    Macias, D., Ganan, Y., Rodriguez-Leon, J., Merino, R., and Hurle, J. M. (1999) Regulation by members of the transforming growth factor beta superfamily of the digital and interdigital fates of the autopodial limb mesoderm. Cell Tissue Res. 296. 95–102.PubMedCrossRefGoogle Scholar
  144. 144.
    Dahn, R. D. and Fallon, J. F. (2000) Interdigital regulation of digit identity and homeotic transformation by modulated BMP signaling. Science 289, 438–441.PubMedCrossRefGoogle Scholar
  145. 145.
    Rizgeliene, R. (1996) Skeleton pattern and joint formation in chorioallantoic grafts lacking the anterior or posterior necrotic zones. J. Anat. 189, 601–608.PubMedGoogle Scholar
  146. 146.
    Nalin, A. M., Greenlee, T. K. Jr., and Sandell, L. J. (1995) Collagen gene expression during development of avian synovial joints: transient expression of types II and XI collagen genes in the joint capsule. Dev. Dyn. 203, 352–362.PubMedCrossRefGoogle Scholar
  147. 147.
    Pizette, S. and Niswander, L. (2000) BMPs are required at two steps of limb chondrogenesis: formation of prechondrogenic condensations and their differentiation into chondrocytes. Dev. Biol. 219, 237–249.PubMedCrossRefGoogle Scholar
  148. 148.
    Pizette, S. and Niswander, L. (1999) BMPs negatively regulate structure and function of the limb apical ectodermal ridge. Development 126, 883–894.PubMedGoogle Scholar
  149. 149.
    Roark, E. F. and Greer, K. (1994) Transforming growth factor-beta and bone morphogenetic protein-2 act by distinct mechanisms to promote chick limb cartilage differentiation in vitro. Dev. Dyn. 200, 103–116.PubMedCrossRefGoogle Scholar
  150. 150.
    Pizette, S., Abate-Shen, C., and Niswander, L. (2001) BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limB. Development 128, 4463–4474.PubMedGoogle Scholar
  151. 151.
    Zhang, H. and Bradley, A. (1996) Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122, 2977–2986.PubMedGoogle Scholar
  152. 152.
    Duprez, D., Bell, E. J., Richardson, M. K., Archer, C. W., Wolpert, L., Brickell, P. M., et al. (1996) Overexpression of BMP-2 and BMP-4 alters the size and shape of developing skeletal elements in the chick limB. Mech. Dev. 57, 145–157.PubMedCrossRefGoogle Scholar
  153. 153.
    Zhang, Z., Yu, X., Zhang, Y., Geronimo, B., Lovlie, A., Fromm, S. H., and Chen, Y. (2000) Targeted misexpression of constitutively active BMP receptor-IB causes bifurcation, duplication, and posterior transformation of digit in mouse limB. Dev. Biol. 220, 154–167.PubMedCrossRefGoogle Scholar
  154. 154.
    Ganan, Y., Macias, D., Duterque-Coquillaud, M., Ros, M. A., and Hurle, J. M. (1996) Role of TGF beta s and BMPs as signals controlling the position of the digits and the areas of interdigital cell death in the developing chick limb autopod. Development 122, 2349–2357.PubMedGoogle Scholar
  155. 155.
    Merino, R., Ganan, Y., Macias, D., Economides, A. N., Sampath, K. T., and Hurle, J. M. (1998) Morphogenesis of digits in the avian limb is controlled by FGFs, TGFbetas, and noggin through BMP signaling. Dev. Biol. 200, 35–45.PubMedCrossRefGoogle Scholar
  156. 156.
    Macias, D., Ganan, Y., Sampath, T. K., Piedra, M. E., Ros, M. A., and Hurle, J. M. (1997) Role of BMP-2 and OP-1 (BMP-7) in programmed cell death and skeletogenesis during chick limb development. Development 124, 1109–1117.PubMedGoogle Scholar
  157. 157.
    Ferrari, D., Lichtler, A. C., Pan, Z. Z., Dealy, C. N., Upholt, W. B., and Kosher, R. A. (1998) Ectopic expression of Msx-2 in posterior limb bud mesoderm impairs limb morphogenesis while inducing BMP-4 expression, inhibiting cell proliferation, and promoting apoptosis. Dev. Biol. 197. 12–24.PubMedCrossRefGoogle Scholar
  158. 158.
    Dencker, L., Gustafson, A. L., Annerwall, E., Busch, C., and Eriksson, U. (1991) Retinoid-binding proteins in craniofacial development. J. Craniofac. Genet. Dev. Biol. 11, 303–314.PubMedGoogle Scholar
  159. 159.
    Lammer, E. J., Chen, D. T., Hoar, R. M., Agnish, N. D., Benke, P. J., Braun, J. T., et al. (1985) Retinoic acid embryopathy. N. Engl. J. Med. 313, 837–841.PubMedCrossRefGoogle Scholar
  160. 160.
    Helms, J. A., Kim, C. H., Eichele, G., and Thaller, C. (1996) Retinoic acid signaling is required during early chick limb development. Development 122, 1385–1394.PubMedGoogle Scholar
  161. 161.
    Helms, J., Thaller, C., and Eichele, G. (1994) Relationship between retinoic acid and sonic hedgehog, two polarizing signals in the chick wing bud. Development 120. 3267–3274.PubMedGoogle Scholar
  162. 162.
    Heller, L. C., Li, Y., Abrams, K. L., and Rogers, M. B. (1999) Transcriptional regulation of the Bmp2 gene. Retinoic acid induction in F9 embryonal carcinoma cells and Saccharomyces cerevisiae. J. Biol. Chem. 274, 1394–1400.PubMedCrossRefGoogle Scholar
  163. 163.
    Francis, P. H., Richardson, M. K., Brickell, P. M., and Tickle, C. (1994) Bone morphogenetic proteins and a signalling pathway that controls patterning in the developing chick limB. Development 120, 209–218.PubMedGoogle Scholar
  164. 164.
    Rodriguez-Leon, J., Merino, R., Macias, D., Ganan, Y., Santesteban, E., and Hurle, J. M. (1999) Retinoic acid regulates programmed cell death through BMP signalling. Nat. Cell Biol. 1, 125–126.PubMedCrossRefGoogle Scholar
  165. 165.
    Weston, A. D., Rosen, V., Chandraratna, R. A., and Underhill, T. M. (2000) Regulation of skeletal progenitor differentiation by the BMP and retinoid signaling pathways. J. Cell Biol. 148, 679–690.PubMedCrossRefGoogle Scholar
  166. 166.
    Ho, A. M., Johnson, M. D., and Kingsley, D. M. (2000) Role of the mouse ank gene in control of tissue calcification and arthritis. Science 289, 265–270.PubMedCrossRefGoogle Scholar
  167. 167.
    Qu, S., Tucker, S. C., Ehrlich, J. S., Levorse, J. M., Flaherty, L. A., Wisdom, R., et al. (1998) Mutations in mouse Aristaless-like4 cause Strong’s luxoid polydactyly. Development 125, 2711–2721.PubMedGoogle Scholar
  168. 168.
    Svensson, L., Aszodi, A., Heinegard, D., Hunziker, E. B., Reinholt, F. P., Fassler, R., et al. (2002) Cartilage oligomeric matrix protein-deficient mice have normal skeletal development. Mol. Cell Biol. 22, 4366–4371.PubMedCrossRefGoogle Scholar
  169. 169.
    Saftig, P., Hunziker, E., Wehmeyer, O., Jones, S., Boyde, A., Rommerskirch, W., et al. (1998) Impaired osteoclastic hone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc. Natl. Acad. Sci. USA 95, 13453–13458.PubMedCrossRefGoogle Scholar
  170. 170.
    Pereira, R., Khillan, J. S., Helminen, H. J., Hume, E. L., and Prockop, D. J. (1993) Transgenic mice expressing a partially deleted gene for type I procollagen (COL1A1) A breeding line with a phenotype of spontaneous fractures and decreased bone collagen and mineral. J. Clin. Invest. 91, 709–716.PubMedCrossRefGoogle Scholar
  171. 171.
    Forlino, A., Porter, F. D., Lee, E. J., Westphal, H., and Marini, J. C. (1999) Use of the Cre/lox recombination system to develop a non-lethal knock- in murine model for osteogenesis imperfecta with an alpha 1(I) G349C substitution. Variability in phenotype in BrtlIV mice. J. Biol. Chem. 274, 37923–37931.PubMedCrossRefGoogle Scholar
  172. 172.
    Helminen, H. J., Kiraly, K., Pelttari, A., Tammi, M. I., Vandenberg, P., Pereira, R., Dhulipala, R., Khillan, J. S., Ala-Kokko, L., Hume, E. L., et al. (1993) An inbred line of transgenic mice expressing an internally deleted gene for type II procollagen (COL2A1) Young mice have a variable phenotype of a chondrodysplasia and older mice have osteoarthritic changes in joints. J. Clin. Invest. 92, 582–595.PubMedCrossRefGoogle Scholar
  173. 173.
    Li, S. W., Prockop, D. J., Helminen, H., Fassler, R., Lapvetelainen, T., Kiraly, K., et al. (1995) Transgenic mice with targeted inactivation of the Co12 alpha 1 gene for collagen II develop a skeleton with membranous and periosteal bone but no endochondral bone. Genes Dev. 9, 2821–2830.PubMedCrossRefGoogle Scholar
  174. 174.
    Lapvetelainen, T., Hyttinen, M., Lindblom, J., Langsjo, T. K., Sironen, R., Li, S. W., et al. (2001) More knee joint osteoarthritis (OA) in mice after inactivation of one allele of type II procollagen gene but less OA after lifelong voluntary wheel running exercise. Osteoarthritis Cartilage 9, 152–160.PubMedCrossRefGoogle Scholar
  175. 175.
    Liu, X., Wu, H., Byrne, M., Krane, S., and Jaenisch, R. (1997) Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. Proc. Natl. Acad. Sci. USA 94, 1852–1856.PubMedCrossRefGoogle Scholar
  176. 176.
    Andrikopoulos, K., Liu, X., Keene, D. R., Jaenisch, R., and Ramirez, F. (1995) Targeted mutation in the col5a2 gene reveals a regulatory role for type V collagen during matrix assembly. Nat. Genet. 9, 31–36.PubMedCrossRefGoogle Scholar
  177. 177.
    Nakata, K., Ono, K., Miyazaki, J., Olsen, B. R., Muragaki, Y., Adachi, E., et al. (1993) Osteoarthritis associated with mild chondrodysplasia in transgenic mice expressing alpha 1(IX) collagen chains with a central deletion. Proc. Natl. Acad. Sci. USA 90, 2870–2874.PubMedCrossRefGoogle Scholar
  178. 178.
    Fassler, R., Schnegelsberg, P. N., Dausman, J., Shinya, T., Muragaki, Y., McCarthy M. T., et al. (1994) Mice lacking alpha 1 (IX) collagen develop noninflammatorv degenerative joint disease. Proc. Natl. Acad. Sci. USA 91, 5070–5074.PubMedCrossRefGoogle Scholar
  179. 179.
    Ting, K., Ramachandran, H., Chung, K. S., Shah-Hosseini, N., Olsen, B. R., and Nishimura, I. (1999) A short isoform of Col9a1 supports alveolar bone repair. Am. J. Pathol. 155, 1993–1999.PubMedCrossRefGoogle Scholar
  180. 180.
    Jacenko, O., LuValle, P. A., and Olsen, B. R. (1993) Spondylometaphyseal dysplasia in mice carrying a dominant negative mutation in a matrix protein specific for cartilage-to-bone transition. Nature 365, 56–61.PubMedCrossRefGoogle Scholar
  181. 181.
    Rosati, R., Horan, G. S., Pinero, G. J., Garofalo, S., Keene, D. R., Horton, W. A., et al. (1994) Normal long bone growth and development in tvoe X collagen-null mice. Nat. Genet. 8, 129–135.PubMedCrossRefGoogle Scholar
  182. 182.
    Gress, C. J. and Jacenko, O. (2000) Growth plate compressions and altered hematopoiesis in collagen X null mice. J. Cell. Biol. 149, 983–993.PubMedCrossRefGoogle Scholar
  183. 183.
    Kwan, K. M., Pang, M. K., Zhou, S., Cowan, S. K., Kong, R. Y., Pfordte, T., et al. (1997) Abnormal compartmentalization of cartilage matrix components in mice lacking collagen X: implications for function. J. Cell. Biol. 136, 459–471.PubMedCrossRefGoogle Scholar
  184. 184.
    Li, Y., Lacerda, D. A., Warman, M. L., Beier, D. R., Yoshioka, H., Ninomiya, Y., et al. (1995) A fibrillar collagen gene, Coll 1al, is essential for skeletal morphogenesis. Cell 80, 423–430.PubMedCrossRefGoogle Scholar
  185. 185.
    Gayraud, B., Keene, D. R., Sakai, L. Y., and Ramirez, F. (2000) New insights into the assembly of extracellular microfibrils from the analysis of the fibrillin 1 mutation in the tight skin mouse. J. Cell. Biol. 150, 667–680.PubMedCrossRefGoogle Scholar
  186. 186.
    Pereira, L., Andrikopoulos, K., Tian, J., Lee, S. Y., Keene, D. R., Ono, R., et al. (1997) Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat. Genet. 17, 218–222.PubMedCrossRefGoogle Scholar
  187. 187.
    Chaudhry, S. S., Gazzard, J., Baldock, C., Dixon, J., Rock, M. J., Skinner, G. C., et al. (2001) Mutation of the gene encoding fibrillin-2 results in syndactyly in mice. Hum. Mol. Genzet. 10, 835–843.CrossRefGoogle Scholar
  188. 188.
    Arteaga-Solis, E., Gayraud, B., Lee, S. Y., Shum, L., Sakai, L., and Ramirez, F. (2001) Regulation of limb patterning by extracellular microfibrils. J. Cell. Biol. 154, 275–281.PubMedCrossRefGoogle Scholar
  189. 189.
    Storm, E. E., Huynh, T. V., Copeland, N. G., Jenkins, N. A., Kingsley, D. M., and Lee, S. J. (1994) Limb alterations in brachypodism mice due to mutations in a new member of the TGF beta-superfamily. Nature 368, 639–643.PubMedCrossRefGoogle Scholar
  190. 190.
    Storm, E. E. and Kingsley, D. M. (1996) Joint patterning defects caused by single and double mutations in members of the bone morphogenetic protein (BMP) family. Developmment 122, 3969–3979.Google Scholar
  191. 191.
    Arikawa-Hirasawa, E., Watanabe, H., Takami, H., Hassell, J. R., and Yamada, Y. (1999) Perlecan is essential for cartilage and cephalic development. Nat. Genet. 23. 354–358.PubMedCrossRefGoogle Scholar
  192. 192.
    Johnson, K. R., Sweet, H. O., Donahue, L. R., Ward-Bailey, P., Bronson, R. T., and Davisson, M. T. (1998) A new spontaneous mouse mutation of Hoxd13 with a polyalanine expansion and phenotype similar to human synpolydactyly. Hum. Mol. Genet. 7, 1033–1038.PubMedCrossRefGoogle Scholar
  193. 193.
    Dolle, P., Dierich, A., LeMeur, M., Schimmang, T., Schuhbaur, B., Chambon, P., and Duboule, D. (1993) Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs. Cell 75, 431–441.PubMedCrossRefGoogle Scholar
  194. 194.
    St-Jacques, B., Hammerschmidt, M., and McMahon, A. P. (1999) Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 13, 2072–2086.PubMedCrossRefGoogle Scholar
  195. 195.
    Hebrok, M., Kim, S. K., St Jacques, B., McMahon, A. P., and Melton, D. A. (2000) Regulation of pancreas development by hedgehog signaling. Development 127, 4905–4913.PubMedGoogle Scholar
  196. 196.
    Liu, Y. H., Kundu, R., Wu, L., Luo, W., Ignelzi, M. A. Jr., Snead, M. L., et al. (1995) Premature suture closure and ectopic cranial bone in mice expressing Msx2 transgenes in the developing skull. Proc. Natl. Acad. Sci. USA 92, 6137–6141.PubMedCrossRefGoogle Scholar
  197. 197.
    Winograd, J., Reilly, M. P., Roe, R., Lutz, J., Laughner, E., Xu, X., et al. (1997) Perinatal lethality and multiple craniofacial malformations in MSX2 transgenic mice. Hum. Mol. Genet. 6, 369–379.PubMedCrossRefGoogle Scholar
  198. 198.
    Satokata, I., Ma, L., Ohshima, H., Bei, M., Woo, I., Nishizawa, K., et al. (2000) Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat. Genet. 24, 391–395.PubMedCrossRefGoogle Scholar
  199. 199.
    McMahon, J. A., Takada, S., Zimmerman, L. B., Fan, C. M., Harland, R. M., and McMahon, A. P. (1998) Nogginmediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev. 12, 1438–1452.PubMedCrossRefGoogle Scholar
  200. 200.
    Brunet, L. J., McMahon, J. A., McMahon, A. P., and Harland, R. M. (1998) Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280, 1455–1457.PubMedCrossRefGoogle Scholar
  201. 201.
    Lanske, B., Karaplis, A. C., Lee, K., Luz, A., Vortkamp, A., Pirro, A., et al. (1996) PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273, 663–666.PubMedCrossRefGoogle Scholar
  202. 202.
    Takeuchi, S., Takeda, K., Oishi, I., Nomi, M., Ikeya, M., Itoh, K., et al. (2000) Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation. Genes Cells 5, 71–78.PubMedCrossRefGoogle Scholar
  203. 203.
    Komori, T., Yagi, H., Nomura, S., Yamaguchi, A., Sasaki, K., Deguchi, K., et al. (1997) Targeted disruption of Cbfa 1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755–764.PubMedCrossRefGoogle Scholar
  204. 204.
    D’Souza, R. N., Aberg, T., Gaikwad, J., Cavender, A., Owen, M., Karsenty, G., et al. (1999) Cbfa 1 is required for epithelial-mesenchymal interactions regulating tooth development in mice. Development 126, 2911–2920.PubMedGoogle Scholar
  205. 205.
    Otto, F., Thorne11, A. P., Crompton, T., Denzel, A., Gilmour, K. C., Rosewell, I. R., et al. (1997) Cbfa 1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765–771.PubMedCrossRefGoogle Scholar
  206. 206.
    Selby, P. B. and Selby, P. R. (1978) Gamma-ray-induced dominant mutations that cause skeletal abnormalities in mice. II. Description of proved mutations. Mutat. Res. 51, 199–236.PubMedCrossRefGoogle Scholar
  207. 207.
    Ducy, P., Starbuck, M., Priemel, M., Shen, J., Pinero, G., Geoffroy, V., et al. (1999) A Cbfa 1 -dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev. 13, 1025–1036.PubMedCrossRefGoogle Scholar
  208. 208.
    Bi, W., Huang, W., Whitworth, D. J., Deng, J. M., Zhang, Z., Behringer, R. R., et al. (2001) Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc. Natl. Acad. Sci. USA 98, 6698–6703.PubMedCrossRefGoogle Scholar
  209. 209.
    Bruneau, B. G., Nemer, G., Schmitt, J. P., Charron, F., Robitaille, L., Caron, S., et al. (2001) A murine model of HoltOram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell 106, 709–721.PubMedCrossRefGoogle Scholar
  210. 210.
    Shull, M. M., Ormsby, I., Kier, A. B., Pawlowski, S., Diebold, R. J., Yin, M., et al. (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359, 693–699.PubMedCrossRefGoogle Scholar
  211. 211.
    Kulkarni, A. B., Huh, C. G., Becker, D., Geiser, A., Lyght, M., Flanders, K. C., et al. (1993) Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90, 770–774.PubMedCrossRefGoogle Scholar
  212. 212.
    Yoshizawa, T., Handa, Y., Uematsu, Y., Takeda, S., Sekine, K., Yoshihara, Y., et al. (1997) Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat. Genet. 16, 391–396.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Lillian Shum
  • Yuji Hatakeyama
  • Julius Leyton
  • Kazuaki Nonaka

There are no affiliations available

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