A1型短指/趾症骨骼发育异常的分子基础研究
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摘要
A1型短指/趾症是人类群体中发现的第一例符合孟德尔遗传规律的常染色体遗传病,患者特征为手/足第二指节的指骨严重缩短或者缺失。近年来,在A1型短指/趾症家系患者中陆续鉴定到了Indian hedgehog (IHH)基因上的多个点突变。目前,人们对于A1型短指/趾症的致病机理仍不清楚。除此之外,人们对Ihh在指骨发育早期所执行的功能的了解也非常有限。为了揭示A1型短指/趾症患者指骨发育异常的原因,并理解E95K突变所导致的分子水平和发育水平变化,我们利用实验室构建的BDA1小鼠模型,从发育生物学和分子生物学角度对A1型短指/趾症致病机理进行了研究。BDA1模型小鼠在Ihh基因上携带等同人类E95K的突变。E95K纯合突变小鼠表现出个体矮小和典型的A1型短指/趾症表型——第二至第四指中指节严重缩短,第五指中指节缺失。同时,和人类患者中一样,E95K突变以显性方式作用于小鼠的指骨表型,使得携带E95K突变的杂合子小鼠也表现出轻微的短指表型。我们利用体外和体内的实验手段研究了E95K突变的分子基础。结果显示,E95K-Ihh的信号能力有一定程度的下降。更为有趣的是,通过体内实验我们发现在突变小鼠的指骨前体和侧肢长骨中,E95K-Ihh的信号作用距离显著增加。在长骨发育中,E95K-Ihh作用距离的改变扰乱了Ihh-PthrP负反馈环,从而影响了软骨细胞的增殖与分化;在指骨前体中,E95K-Ihh作用距离的增加使得更多的Ihh信号进入到中间区,并刺激了PthrP——一种指骨前体中Ihh表达的潜在调控因子——在中间区的表达。进一步的研究表明,E95K突变导致BDA1小鼠指骨前体远端的Ihh信号水平下降,并导致指放线远端间叶细胞吸纳的减缓,从而阻碍了指骨前体向远端的生长。这种生长减缓导致指骨前体尺寸减小,从而使得突变小鼠第二指节和第三指节分节异常。另外,我们观察到BDA1小鼠指骨关节中间区发育的延迟和异常。Ihh基因敲除小鼠的指骨表型表明,在Ihh功能缺失的情况下,指骨远端生长严重受损,中间区发育失败。我们的结果说明Ihh信号在指骨发育早期调控指放线的远端生长,并可能参与指骨关节中间区的早期发育调控。
Brachydactyly type A1 (BDA1; MIM 112500), characterized by shortening or absence of the middle phalanges in digits, is the first recorded disorder of the autosomal dominant Mendelian trait in human. Recently, heterozygous missense mutations in the Indian hedgehog gene (IHH) were reported for BDA1. However, the underlying pathogenesis of BDA1 and the role of Ihh during early digit morphogenesis were remained unclear. As it is a developmental abnormality, we carefully studied a mouse model carrying a human equivalent E95K missense mutation to address the molecular and developmental consequences. Homozygous mice for the E95K allele displayed mild dwarfism and typical characteristics of BDA1 with severe shortening (digit II-IV) or missing (digit V) of the middle phalanges. Moreover, like in human cases, this mutation exerts a dominant effect in mice, causing mild brachydactyly type A1 phenotype in Ihh+/E95K mice. We studied the molecular basis of the E95K mutation in vitro and in vivo. Our results suggest that there is a slight reduction in the signaling capacity of the E95K Ihh protein, but the effective signaling range in the cartilage element of the developing digits and long bones is broader. In long bones, the alteration in the signaling range of Ihh signal disturbs the Ihh-PthrP negative feedback loop and impairs chondrocyte proliferation and differentiation. In digits, this increased Ihh signaling range allows additional signals extend into the interzone and enhance PthrP expression, a potential negative feedback regulator of Ihh expression. We further showed that distal Ihh signal is reduced in BDA1 mice, impairing mesenchymal recruitment and growth of the distal cartilage element, contributing to the abnormal segmentation between the middle and distal phalanges causing BDA1. In addition, inter-phalangeal interzone development is abnormal in BDA1 mice. In support of these observations, we show that the distal outgrowth and interzone development of digital primordia are almost completely abolished in the digital context correspond to Ihh signaling. Thus, our results suggest that IHH signaling is needed in regulating elongation of distal digit elements during early digit patterning.
Brachydactyly type A1 (BDA1; MIM 112500), characterized by shortening or absence of the middle phalanges in digits, is the first recorded disorder of the autosomal dominant Mendelian trait in human. Recently, heterozygous missense mutations in the Indian hedgehog gene (IHH) were reported for BDA1. However, the underlying pathogenesis of BDA1 and the role of Ihh during early digit morphogenesis were remained unclear. As it is a developmental abnormality, we carefully studied a mouse model carrying a human equivalent E95K missense mutation to address the molecular and developmental consequences. Homozygous mice for the E95K allele displayed mild dwarfism and typical characteristics of BDA1 with severe shortening (digit II-IV) or missing (digit V) of the middle phalanges. Moreover, like in human cases, this mutation exerts a dominant effect in mice, causing mild brachydactyly type A1 phenotype in Ihh+/E95K mice. We studied the molecular basis of the E95K mutation in vitro and in vivo. Our results suggest that there is a slight reduction in the signaling capacity of the E95K Ihh protein, but the effective signaling range in the cartilage element of the developing digits and long bones is broader. In long bones, the alteration in the signaling range of Ihh signal disturbs the Ihh-PthrP negative feedback loop and impairs chondrocyte proliferation and differentiation. In digits, this increased Ihh signaling range allows additional signals extend into the interzone and enhance PthrP expression, a potential negative feedback regulator of Ihh expression. We further showed that distal Ihh signal is reduced in BDA1 mice, impairing mesenchymal recruitment and growth of the distal cartilage element, contributing to the abnormal segmentation between the middle and distal phalanges causing BDA1. In addition, inter-phalangeal interzone development is abnormal in BDA1 mice. In support of these observations, we show that the distal outgrowth and interzone development of digital primordia are almost completely abolished in the digital context correspond to Ihh signaling. Thus, our results suggest that IHH signaling is needed in regulating elongation of distal digit elements during early digit patterning.
引文
1. http://en.wikipedia.org/wiki/Brachydactyly
2. Bell, J. On brachydactyly and symphalangism. In: Penrose, L. S.: Treasury of Human Inheritance. London: Cambridge Univ. Press (pub.) 5 1951. Pp. 1-31.
3. http://www.peds.ufl.edu/PEDS2/divisions/genetics/caw/resources_other_malfor mations.htm
4. http://en.wikipedia.org/wiki/William_Curtis_Farabee
5. Farabee, W. C. Hereditary and sexual influence in meristic variation: a study of digital malformations in man. Ph.D. Thesis: Harvard Univ. (pub.) 1903.
6. Drinkwater, H. A second brachydactylous family. J Genet 1914; 4: 323-339.
7. Drinkwater, H. An account of a brachydactylous family. Proc Royal Soc Edin 1908; 28: 35-57.
8. Drinkwater, H. Account of a family showing minor-brachydactyly. J Genet 1912; 2: 21-40.
9. Yang, X.P., She, C.W., Guo, J.Z. et al. A locus for brachydactyly type A-1 maps to chromosome 2q35-q36. Am J Hum Genet 2000; 66: 892-903.
10. Gao, B., Guo, J.Z., She, C.W. et al. Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1. Nat Genet 2001; 28: 386-388.
11. McCready, M.E., Sweeney, E., Fryer, A.E. et al. A novel mutation in the IHH gene causes brachydactyly type A1: a 95-year-old mystery resolved. Hum Genet 2002; 111: 368–375.
12.McCready, M.E., Grimsey, A., Styer, T. et al. A century later Farabee has his mutation. Hum Genet 2005; 117(2-3): 285-7.
13. Kirkpatrick, T.J., Au, K.S., Mastrobattista, J.M. et al. Identification of a mutation in the Indian Hedgehog (IHH) gene causing brachydactyly type A1 and evidence for a third locus. J Med Genet 2003; 40(1): 42-4.
14. Giordano, N., Gennari, L., Bruttini, M. et al. Mild brachydactyly type A1 maps to chromosome 2q35-q36 and is caused by a novel IHH mutation in a three generation family. J Med Genet 2003; 40(2): 132-5.
15. Hellemans, J., Coucke, P.J., Giedion, A. et al. Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. Am J Hum Genet 2003; 72(4): 1040-6.
16. Liu, M.G., Wang, X., Cai, Z. et al. A novel heterozygous mutation in the Indian hedgehog gene (IHH) is associated with brachydactyly type A1 in a Chinese family. J Hum Genet 2006; 51: 727–731.
17. http://www.med.unc.edu/embryo_images/
18. Niswander, L. Pattern formation: old models out on a limb. Nat Rev Genet 2003; 4: 133-43. Review.
19. Saunders, J. W. Jr. The proximo-distal sequence of origin of the parts of the chick wing and the role of the ectoderm. J Exp Zool 1948; 108: 363–403.
20. Summerbell, D. A quantitative analysis of the effect of excision of the AER from the chick limb-bud. J Embryol Exp Morphol 1974; 32: 651–660.
21. Ahn, K. et al. BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal/ventral patterning of the limb. Development 2001; 128: 4449–4461.
22. Pizette, S., Abate-Shen, C. & Niswander, L. BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb. Development 2001; 128: 4463–4474.
23. Kawakami, Y. et al. WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo. Cell 2001; 104: 891–900.
24. Min, H. et al. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev 1998; 12: 3156–3161.
25. Sekine, K. et al. Fgf10 is essential for limb and lung formation. Nature Genet 1999; 21: 138–141.
26. Altabef, M., Clarke, J. D. W. & Tickle, C. Dorso-ventral ectodermal compartments and origin of apical ectodermal ridge in developing chick limb. Development 1997; 124: 4547–4556.
27. Kimmel, R. A. et al. Two lineage boundaries coordinate vertebrate apical ectodermal ridge formation. Genes Dev 2000; 14: 1377–1389.
28.Rubin, L. and Saunders, J. W. J. Ectodermal-mesodermal interactions in the growth of limb buds in the chick embryo: constancy and temporal limits of the ectodermal induction. Dev Biol 1972; 28: 94–112.
29. Niswander, L. et al. FGF-4 replaces the apical ectodermal ridge and direct outgrowth and patterning of the limb. Cell 1993; 75: 579–587.
30. Fallon, J. F. et al. FGF-2: apical ectodermal ridge growth signal for chick limb development. Science 1994; 264: 104–107.
31. Sun, X., Mariani, F. V. & Martin, G. R. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature 2002; 418: 501–508.
32. Pizette, S. & Niswander, L. BMPs negatively regulate structure and function of the limb apical ectodermal ridge. Development 1999; 126: 883–894.
33. Saunders, J. W. Jr & Gasseling, M. T. in Epithelial-Mesenchymal Interactions (eds Fleischmajer, R. & Billingham, R. E.) 78-97 (Williams and Wilkins, Baltimore, 1968).
34. Tickle, C. The number of polarizing region cells required to specify additional digits in the developing chick wing. Nature 1981; 289: 295–298.
35. Tickle, C. et al. Local application of retinoic acid to the limb bud mimics the action of the polarizing region. Nature 1982; 296: 564–565.
36. Helms, J., Thaller, C. and Eichele, G. Relationship between retinoic acid and sonic hedgehog, two polarizing signals in the chick wing bud. Development 1994; 120: 3267–3274.
37. Helms, J. A. et al. Retinoic acid signaling is required during early chick limbdevelopment. Development 1996; 122: 1385–1394 .
38. Stratford, T., Horton, C. & Maden, M. Retinoic acid is required for the initiation of outgrowth in the chick limb bud. Curr Biol 1996; 6: 1124–1133.
39. Lu, H.C. et al. Retinoid signaling is required for the establishment of a ZPA and for the expression of Hoxb-8, a mediator of ZPA formation. Development 1997; 124: 1643–1651.
40. Niederreither, K. et al. Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse. Development 2002; 129: 3563–3574.
41. Riddle, R. D. et al. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 1993; 75: 1401–1416.
42. Chiang, C. et al. Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. Dev Biol 2001; 236: 421–435.
43. Kraus, P., Fraidenraich, D. and Loomis, C. A. Some distal limb structures develop in mice lacking Sonic Hedgehog signaling. Mech Dev 2001; 100: 45–58.
44. Sanz-Ezquerro JJ and Tickle C. Digital development and morphogenesis. J Anat 2003; 202: 51-8.
45. Smith, J.C., Tickle, C. and Wolpert, L. Attenuation of positional signalling in the chicklimb by high doses of gamma radiation. Nature 1978; 272: 612–613.
46. Smith, J. The time required for positional signalling in the chick wing bud. J Embryol Exp Morph 1980; 60: 321–328.
47. Tickle, C. The number of polarizing region cells required to specify additional digits in the developing chick wing. Nature 1981; 289: 295–298.
48. Lee, J. and Tickle, C. Retinoic acid and pattern formation in the developing chick wing. SEM and quantitative studies of early effects on the apical ectodermal ridge and bud outgrowth. J Embryol Exp Morph 1985; 90: 139–169.
49. Brickell, P.M. and Tickle, C. Morphogens in chick limb development. Bioessays 1989; 11: 145–149.
50. Vargesson, N., Clarke, J.D.W., Vincent, K., Coles, C., Wolpert, L. and Tickle, C. Cell fate in the chick limb bud and relationship to gene expression. Development 1997; 124: 1909–1918.
51. Dahn, R.D. and Fallon, J.F. Interdigital regulation of digit identity and homeotic transformation by modulated BMP signaling. Science 2000; 289: 438–441.
52. Sanz-Ezquerro, J.J. and Tickle, C. Autoregulation of Shh expression and Shh induction of cell death suggest a mechanism for modulating polarising activity during chick limb development. Development 2000; 127: 4811–4823.
53. Ganan, Y. Role of TGF betas and BMPs as signals controlling the position of the digits and the areas of interdigital cell death in the developing chick limb autopod. Development 1996; 122: 2349–2357.
54. Hurle, J.M. and Ganan, Y. Interdigital tissue chondrogenesis induced by surgical removal of the ectoderm in the embryonic chick leg bud. J Embryol Exp Morph 1986; 94: 231–244.
55. Omi, M., Sato-Maeda, M. and Ide, H. Role of chondrogenic tissue in programmed cell death and BMP expression in chick limb buds. Int J Dev Biol 2000; 44: 381–388.
56. Cecconi, F., Alvarez-Bolado, G., Meyer, B.I., Roth, K.A. and Gruss, P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 1998; 94: 727–737.
57. Lindsten, T., Ross, A.J., King, A., Zong, W.X., Rathmell, J.C., Shiels, H.A., et al. The combined functions of proapoptic Bc1–2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 2000; 6: 1389–1399.
58. Francis-West, P.H., Parish, J., Lee, K. and Archer, C.W. BMP/GDF–signalling interactions during synovial joint development. Cell Tissue Res 1999; 296: 111–119.
59. Yokouchi, Y., Sasaki, H., Kuroiwa, A. Homeobox gene expression correlates with the bifurcation process of limb cartilage development. Nature 1991; 353: 443–445.
60. Khoa, N.D., Hasunuma, T., Kobata, T., et al. Expression of murine HOXD9 during embryonic joint patterning and in human T lymphotropic virus type I tax transgenic mice with arthropathy resembling rheumatoid arthritis. Arthr Rheum 1999; 42: 686–696.
61. Fromental-Ramain, C., Warot, X., Messadecq, N., et al. Hoxa-13 and Hod-13 play a crucial role in the patterning of the limb autopod. Development 1996; 122: 2997–3011.
62. Mitrovic, D. Development of the metatarsalphalangeal joint of the chick embryo: Morphological, ultrastructural and histochemical studies. A J Anat 1977; 150: 333–348.
63. Storm, E.E., Kingsley, D.M. GDF5 coordinates bone and joint formation during digit development. Dev Biol 1999; 209: 11–27.
64. Francis-West, P.H., Abdelfattah, A., Chen, P., et al. Mechanisms of GDF-5 action during skeletal development. Development 1999; 126: 1305–1315.
65. Merino, R., Macias, D., Ganan, Y., et al. Expression and function of GDF-5 during digit skeletogenesis in the embryonic chick leg bud. Dev Biol 1999; 206: 33–45.
66. Hartmann, C., Tabin, C.J. Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton. Cell 2001; 104: 341–351.
67. Guo, X., Day, T.F., Jiang, X., Garrett-Beal, L., Topol, L., Yang, Y. Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation. Genes Dev 2004; 18(19): 2404-17.
68. Sp?ter, D., Hill, T.P., O'sullivan, R.J., Gruber, M., Conner, D.A., Hartmann, C. Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis. Development 2006; 133(15): 3039-49.
69. Spagnoli, A., O'Rear, L., Chandler, R.L., Granero-Molto, F., Mortlock, D.P., Gorska, A.E., Weis, J.A., Longobardi, L., Chytil, A., Shimer, K., Moses, H.L. TGF-beta signaling is essential for joint morphogenesis. J Cell Biol 2007; 177(6): 1105-17.
70. Borgens, R.B. Mice regrow the tips of their foretoes. Science 1982; 217: 747–750.
71. Reginelli, A.D., Wang, Y.Q., Sassoon, D., and Muneoka, K. Digit tip regeneration correlates with regions of Msx1 (Hox7) expression in fetal and newborn mice. Development 1995; 121: 1065–1076.
72. Pacifici, M., Liu, M., and Koyama, E. Joint formation: new findings shed more light on this critical process in skeletogenesis. Current Opinion in Orthopaedics 2002; 13: 339–344.
73. Hall, B.K. and Miyake, T. All for one and one for all: condensations and the initiation of skeletal development. BioEsssays 2000; 22: 138–147.
74. Kronenberg, H.M. Developmental regulation of the growth plate. Nature 2003; 423(6937): 332-6.
75. Noonan, K.J., Hunziker, E.B., Nessler, J. and Buckwalter, J.A. Changes in cell, matrix compartment, and fibrillar collagen volumes between growth-plate zones. J Orthop Res 1998; 16: 500–508.
76. St-Jacques, B., Hammerschmidt, M. and McMahon, A.P. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 1999; 13: 2072–2086. [Published erratum appears in Genes Dev 1999; 13: 2617.]
77. Long, F., Zhang, X.M., Karp, S., Yang, Y. and McMahon, A.P. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 2001; 128: 5099–5108.
78. Karaplis, A. C. et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormonerelated peptide gene. Genes Dev 1994; 8: 277–289.
79. Lanske, B. et al. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 1996; 273: 663–666.
80. Weir, E. C. et al. Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation. Proc Natl Acad Sci 1996; 93: 10240–10245.
81. Schipani, E. et al. Targeted expression of constitutively active receptors for parathyroid hormone and parathyroid hormone-related peptide delays endochondral bone formation and rescues mice that lack parathyroid hormone-related peptide. Proc Natl Acad Sci USA 1997; 94: 13689–13694.
82. Karp, S.J. et al. Indian Hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent. Development 2000; 127: 543–548.
83. Vortkamp, A. et al. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH related protein. Science 1996; 273: 613–622.
84. Chung, U.I., Lanske, B., Lee, K., Li, E. and Kronenberg, H. The parathyroid hormone/parathyroid hormone-related peptide receptor coordinates endochondral bone development by directly controlling chondrocyte differentiation. Proc Natl Acad Sci USA 1998; 95: 13030–13035.
85. Chung, U.I., Schipani, E., McMahon, A.P. and Kronenberg, H.M. Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. J Clin Invest 2001; 107: 295–304.
86. Ornitz, D. M. and Marie, P. J. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 2002; 16: 1446–1465.
87. Murakami, S., Kan, M., McKeehan, W. L. and de Crombrugghe, B. Up-regulationof the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. Proc Natl Acad Sci USA 2000; 97: 1113–1118.
88. Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A. and Leder, P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 1996; 84: 911–921.
89. Colvin, J. S., Bohne, B. A., Harding, G. W., McEwen, D. G. and Ornitz, D. M. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genet 1996; 12: 390–397.
90. Naski, M. C., Colvin, J. S., Coffin, J. D. and Ornitz, D. M. Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 1998; 125: 4977–4988.
91. Sahni, M. et al. FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev 1999; 13: 1361–1366.
92. Liu, Z., Xu, J., Colvin, J. S. and Ornitz, D. M. Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev 2002; 16: 859–869.
93. Ohbayashi, N. et al. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev 2002; 16: 870–879.
94. Minina, E., Kreschel, C., Naski, M. C., Ornitz, D. M. and Vortkamp, A. Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev Cell 2002; 3: 439–449.
95. Rosen, V. and Wozney, J. M. in Principles of Bone Biology (eds Bilezikian, J. P.,Raisz, L. G. & Rodan, G. A.) 919–928 (Academic, San Diego, 2002).
96. Pizette, S. and Niswander, L. BMPs are required at two steps of limb chondrogenesis: formation of prechondrogenic condensations and their differentiation into chondrocytes. Dev Biol 2000; 219: 237–249.
97. Brunet, L.J., McMahon, J.A., McMahon, A.P. and Harland, R.M. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 1998; 280: 1455–1458.
98. Kingsley, D.M. et al. The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGF beta superfamily. Cell 1992; 71: 399–410.
99. Yi, S.E., Daluiski, A., Pederson, R., Rosen, V. and Lyons, K. M. The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. Development 2000; 127: 621–630.
100. Baur, S.T., Mai, J.J. and Dymecki, S.M. Combinatorial signaling through BMP receptor IB and GDF5: shaping of the distal mouse limb and the genetics of distal limb diversity. Development 2000; 127: 605–619.
101. Minina, E. et al. BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation anddifferentiation. Development 2001; 128: 4523–4534.
102. Bi, W., Deng, J. M., Zhang, Z., Behringer, R.R. and de Crombrugghe, B. Sox9 is required for cartilage formation. Nature Genet 1999; 22: 85–89.
103. Akiyama, H., Chaboissier, M. C., Martin, J. F., Schedl, A. and de Crombrugghe, B. The transcription factor Sox9 has essential roles in successive steps of thechondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 2002; 16: 2813–2828.
104. Smits, P. et al. The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev Cell 2001; 1: 277–290.
105. Otto, F. et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 1997; 89: 765–771.
106. Komori, T. et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997; 89: 755–764.
107. Inada, M. et al.Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev Dyn 1999; 214: 279–290.
108. Takeda, S., Bonnamy, J.P., Owen, M.J., Ducy, P. and Karsenty, G. Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. Genes Dev 2001; 15: 467–481.
109. Ueta, C. et al. Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J Cell Biol 2001; 153: 87–100.
110. Nusslein-Volhard, C. and Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 1980; 287: 795–801.
111. McMahon, A.P., Ingham, P.W. and Tabin, C.J. Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 2003; 53: 1–114.
112. Chiang C, Litingtung Y, Lee E, et al. Cyclopia and defective axial patterning inmice lacking Sonic hedgehog gene function. Nature, 1996, 383:407–13
113. Bitgood, M.J., McMahon, A.P. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev. Biol. 1995;172: 126-138.
114. Baron, M. H. Embryonic origins of mammalian hematopoiesis. Exp Hematol 2003; 31: 1160–1169.
115. Machold, R. et al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 2003; 39: 937–950.
116. Palma, V. and Ruiz i Altaba, A. Hedgehog–GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development 2004; 131: 337–345.
117. Adolphe, C. et al. An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Development 2004; 131: 5009–5019.
118. Maye, P. et al. Hedgehog signaling is required for the differentiation of ES cells into neurectoderm. Dev Biol 2004; 265: 276–290.
119. Pasca di Magliano, M. and Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nature Rev Cancer 2003; 3: 903–911.
120. Lum, L. and Beachy, P.A. The Hedgehog response network: sensors, switches, and routers. Science 2004; 304: 1755–1759.
121. Lee, J.J., et al. Autoproteolysis in hedgehog protein biogenesis. Science 1994;266: 1528–1537.
122. Bumcrot, D.A., Takata, R., and McMahon, A.P. Proteolytic processing yields two secreted forms of Sonic hedgehog. Mol Cell Biol 1995; 15: 2294–2303.
123. Chu, T., Chiu, M., Zhang, E., Kunes, S. A C-terminal motif targets Hedgehog to axons, coordinating assembly of the Drosophila eye and brain. Dev Cell 2006; 10: 635-646.
124. Miao-Hsueh, Chen., Ya-Jun, Li., Takatoshi, Kawakami., Shan-Mei, Xu. and Pao-Tien, Chuang. Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes & Dev 2004; 18: 641-659
125. Burke, R., Nellen, D., Bellotto, M., Hafen, E., Senti, K.A., Dickson, B.J., Basler, K. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell 1999; 99: 803-815.
126. Lewis, P.M., Dunn, M.P., McMahon, J.A., Logan, M., Martin, J.F., St-Jacques, B., McMahon, A.P. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 2001; 105: 599-612.
127. Yina, Li., Huimin, Zhang., Ying, Litingtung., and Chin, Chiang. Cholesterol modification restricts the spread of Shh gradient in the limb bud. Proc Natl Acad Sci USA 2006; 103: 6548–6553.
128. Panakova, D., Sprong, H., Marois, E., Thiele, C., Eaton, S. Lipoprotein particles are required for Hedgehog and Wingless signalling. Nature 2005; 435: 58-65.
129. Tanaka, Y., Okada, Y., Hirokawa, N. FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination. Nature 2005; 435: 172-177.
130. http://upload.wikimedia.org/wikipedia/commons/archive/5/55/20070124120537!Shh_processing.png
131. Rohatgi, R., Scott, M.P. Patching the gaps in Hedgehog signalling. Nat Cell Biol 2007; 9(9): 1005-1009.
132. Chen, Y., Struhl, G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 1996; 87(3): 553-63.
133. Chuang, P.T., McMahon, A.P. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999; 397(6720): 617-21.
134. Tenzen, T., Allen, B.L., Cole, F., Kang, J.S., Krauss, R.S., McMahon, A.P. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell 2006; 10: 647-656.
135. Yao, S., Lum, L., Beachy, P. The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell 2006; 125: 343-357.
136. Zhang, W., Kang, J.S., Cole, F., Yi, M.J., Krauss, R.S. Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev Cell 2006; 10: 657-665.
137. Takei, Y., Ozawa, Y., Sato, M., Watanabe, A., Tabata, T. Three Drosophila EXTgenes shape morphogen gradients through synthesis of heparan sulfate proteoglycans. Development 2004; 131: 73–82.
138. Bornemann, D.J., Duncan, J.E., Staatz, W., Selleck, S., Warrior, R.. Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways. Development 2004; 131: 1927–1938.
139. Koziel, L., Kunath, M., Kelly, O.G., Vortkamp, A. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell 2004; 6: 801–813.
140. Glise, B., Miller, C.A., Crozatier, M., Halbisen, M.A., Wise, S., Olson, D.J., Vincent, A., Blair, S.S. Shifted, the Drosophila ortholog of Wnt inhibitory factor-1, controls the distribution and movement of Hedgehog. Dev Cell 2005; 8: 255-266.
141. Gorfinkiel, N., Sierra, J., Callejo, A., Ibanez, C., Guerrero, I. The Drosophila ortholog of the human Wnt inhibitor factor Shifted controls the diffusion of lipid-modified Hedgehog. Dev Cell 2005; 8: 241-253.
142. Hollway, G.E., Maule, J., Gautier, P., Evans, T.M., Keenan, D.G., Lohs, C., Fischer, D., Wicking, C., Currie, P.D. Scube2 mediates Hedgehog signalling in the zebrafish embryo. Dev Biol 2006; 294: 104-118.
143. Kawakami, A., Nojima, Y., Toyoda, A., Takahoko, M., Satoh, M., Tanaka, H., Wada, H., Masai, I., Terasaki, H., Sakaki, Y. et al. The zebrafish-secreted matrix protein you/scube2 is implicated in long-range regulation of hedgehog signaling. Curr Biol 2005; 15: 480-488.
144. Woods, I.G., Talbot, W.S. The you gene encodes an EGF-CUB protein essential for Hedgehog signaling in zebrafish. PLoS Biol 2005; 3: e66.
145. Reiter, J.F., Skarnes, W.C. Tectonic, a novel regulator of the Hedgehog pathway required for both activation and inhibition. Genes Dev 2006; 20: 22-27.
146. Chen, J.K., Taipale, J., Cooper, M.K., Beachy, P.A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002; 16: 2743-2748.
147. Sinha, S., Chen, J.K. Purmorphamine activates the Hedgehog pathway by targeting Smoothened. Nat Chem Biol 2006; 2: 29-30.
148. Bijlsma, M.F., Spek, C.A., Zivkovic, D., van de Water, S., Rezaee, F., Peppelenbosch, M.P. Repression of Smoothened by patcheddependent (pro-)vitamin D3 secretion. PLoS Biol 2006; 4: e232.
149. Corcoran, R.B., Scott, M.P. Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci USA 2006; 103: 8408-8413.
150. Stegman, M. A. et al. The Kinesin-related protein Costal2 associates with membranes in a Hedgehog-sensitive, Smoothened-independent manner. J Biol Chem 2004; 279: 7064–7071.
151. Robbins, D.J. et al. Hedgehog elicits signal transduction by means of a large complex containing the kinesinrelated protein costal2. Cell 1997; 90: 225–234.
152. Sisson, J.C., Ho, K.S., Suyama, K. and Scott, M.P. Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway. Cell 1997; 90: 235–245.
153. Zhang, W. et al. Hedgehog-regulated costal2-kinase complexes control phosphorylation and proteolytic processing of cubitus interruptus. Dev Cell 2005; 8: 267–278.
154. Jiang, J. and Struhl, G. Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 1998; 391: 493–496.
155. Dai, P., Akimaru, H., and Ishii, S. A hedgehog-responsive region in the Drosophila wing disc is defined by debramediated ubiquitination and lysosomal degradation of Ci. Dev Cell 2003; 4: 917–928.
156. Lum, L. et al. Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2. Mol Cell 2003; 12: 1261–1274.
157. Methot, N. and Basler, K. Suppressor of Fused opposes Hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development 2000; 127: 4001–4210.
158. Cheng, S.Y. and Bishop, J.M. Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18–mSin3 corepressor complex. Proc Natl Acad Sci USA 2002; 99: 5442–5447.
159. Merchant, M. et al. Suppressor of fused regulates Gli activity through a dual binding mechanism. Mol Cell Biol 2004; 24: 8627–8641.
160. Jia, J., Tong, C., Wang, B., Luo, L. and Jiang, J. Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase 1. Nature 2005; 432: 1045–1050.
161. Apionishev, S., Katanayeva, N.M., Marks, S.A., Kalderon, D. and Tomlinson, A. Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Nature Cell Biol 2005; 7: 86–92.
162. Zhang, C., Williams, E. H., Guo, Y., Lum, L. and Beachy, P. A. Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc Natl Acad Sci USA 2004; 101: 17900–17907.
163. Stegman, M.A. et al. Identification of a tetrameric hedgehog signaling complex. J Biol Chem 2000; 275: 21809–21812.
164. Rahnama, F., Toftgard, R. and Zaphiropoulos, P.G. Distinct roles of PTCH2 splice variants in Hedgehog signalling. Biochem. J. 2004; 378: 325–334.
165. Tay, S.Y., Ingham, P.W., Roy, S. A homologue of the Drosophila kinesin-like protein Costal2 regulates Hedgehog signal transduction in the vertebrate embryo. Development 2005; 132: 625-634.
166. Varjosalo, M., Li, S.P., Taipale, J. Divergence of hedgehog signal transduction mechanism between Drosophila and mammals. Dev Cell 2006; 10: 177-186.
167. Corbit, K.C., Aanstad, P., Singla, V., Norman, A.R., Stainier, D.Y., Reiter, J.F. Vertebrate Smoothened functions at the primary cilium. Nature 2005; 437: 1018-1021.
168. Haycraft, C.J., Banizs, B., Aydin-Son, Y., Zhang, Q., Michaud, E.J., Yoder, B.K. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 2005; 1: e53.
169. Huangfu, D., Anderson, K.V. Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci USA 2005; 102: 11325-11330.
170. Huangfu, D., Liu, A., Rakeman, A.S., Murcia, N.S., Niswander, L., Anderson, K.V. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 2003; 426: 83-87.
171. Liu, A., Wang, B., Niswander, L.A. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development 2005; 132: 3103-3111.
172. Cooper, A.F., Yu, K.P., Brueckner, M., Brailey, L.L., Johnson, L., McGrath, J.M., Bale, A.E. Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Development 2005; 132: 4407-4417.
173. Koudijs, M.J., den Broeder, M.J., Keijser, A., Wienholds, E., Houwing, S., van Rooijen, E.M., Geisler, R., van Eeden, F.J. The zebrafish mutants dre, uki, and lep encode negative regulators of the hedgehog signaling pathway. PLoS Genet 2005; 1: e19.
174. Svard, J., Heby-Henricson, K., Persson-Lek, M., Rozell, B., Lauth, M., Bergstrom, A., Ericson, J., Toftgard, R., Teglund, S. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell 2006; 10: 187-197.
175. Preat, T., Therond, P., Limbourg-Bouchon, B., Pham, A., Tricoire, H., Busson, D., Lamour-Isnard, C. Segmental polarity in Drosophila melanogaster: genetic dissection of fused in a Suppressor of fused background reveals interaction with costal-2. Genetics 1993; 135: 1047-1062.
176. Chen, M.H., Gao, N., Kawakami, T., Chuang, P.T. Mice deficient in the fused homolog do not exhibit phenotypes indicative of perturbed hedgehog signaling during embryonic development. Mol Cell Biol 2005; 25: 7042-7053.
177. Merchant, M., Evangelista, M., Luoh, S.M., Frantz, G.D., Chalasani, S., Carano, R.A., van Hoy, M., Ramirez, J., Ogasawara, A.K., McFarland, L.M. et al. Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol Cell Biol 2005; 25: 7054-7068.
178. Wolff, C., Roy, S., Ingham, P.W. Multiple muscle cell identities induced by distinct levels and timing of hedgehog activity in the zebrafish embryo. Curr Biol 2003; 13: 1169-1181.
179. Karlstrom, R.O., Tyurina, O.V., Kawakami, A., Nishioka, N., Talbot, W.S., Sasaki, H., Schier, A.F. Genetic analysis of zebrafish gli1 and gli2 reveals divergent requirements for gli genes in vertebrate development. Development 2003; 130: 1549-1564.
180. Zhang, W., Zhao, Y., Tong, C., Wang, G., Wang, B., Jia, J., Jiang, J. Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Dev Cell 2005; 8: 267-278.
181. Jia, J., Zhang, L., Zhang, Q., Tong, C., Wang, B., Hou, F., Amanai, K., Jiang, J. Phosphorylation by double-time/CKIe and CKIa targets cubitus interruptus for Slimb/b-TRCP-mediated proteolytic processing. Dev Cell 2005; 9: 819-830.
182. Smelkinson, M.G., Kalderon, D. Processing of the Drosophila hedgehog signaling effector Ci-155 to the repressor Ci-75 is mediated by direct binding to the SCF component Slimb. Curr Biol 2006; 16: 110-116.
183. Tempe, D., Casas, M., Karaz, S., Blanchet-Tournier, M.F., Concordet, J.P. Multisite protein kinase A and glycogen synthase kinase 3b phosphorylation leads to Gli3 ubiquitination by SCF?TrCP. Mol Cell Biol 2006; 26: 4316-4326.
184. Wang, B., Li, Y. Evidence for the direct involvement of bTrCP in Gli3 protein processing. Proc Natl Acad Sci USA 2006; 103: 33-38.
185. Pan, Y., Bai, C.B., Joyner, A.L., Wang, B. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol 2006; 26: 3365-3377.
186. Huntzicker, E.G., Estay, I.S., Zhen, H., Lokteva, L.A., Jackson, P.K., Oro, A.E. Dual degradation signals control Gli protein stability and tumor formation. Genes Dev 2006; 20: 276-281.
187. Zhang, Q., Zhang, L., Wang, B., Ou, C.Y., Chien, C.T., Jiang, J. A hedgehog-induced BTB protein modulates hedgehog signaling by degrading Ci/Gli transcription factor. Dev Cell 2006; 10: 719-729.
188. Riobo, N.A., Lu, K., Ai, X., Haines, G.M., Emerson, C.P.Jr. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc Natl Acad Sci USA 2006; 103: 4505-4510.
189. Davey MG, Paton IR, Yin Y, Schmidt M, Bangs FK, Morrice DR, Smith TG, Buxton P, Stamataki D, Tanaka M et al. The chicken talpid3 gene encodes a novel protein essential for Hedgehog signaling. Genes Dev 2006; 20: 1365-1377.
190. Hooper, J.E., Scott, M.P. Communicating with Hedgehogs. Nat Rev Mol Cell Biol 2005; 6(4): 306-17.
191. Bo Gao. Developmental Genetics of the Distal Skeletal Elements of Limbs in Vertebrate Based on Brachydactyly Type A1 (BDA1). Dissertation 2005; SJTU.
192. Haaf, T. High-resolution analysis of DNA replication in released chromatin fibers containing 5-bromodeoxyuridine. Biotechniques 1996; 21: 1050-4.
193. Schmahl, J., Eicher, E.M., Washburn, L.L., and Capel, B. Sry induces cell proliferation in the mouse gonad. Development 2000. 127: 65-73.
194. Basler, K., and Struhl, G. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 1994. 368: 208-14.
195. Tabata, T., and Kornberg, T.B. Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell 1994. 76: 89-102.
196. Seo, H.S., and Serra, R. Deletion of Tgfbr2 in Prx1-cre expressing mesenchyme results in defects in development of the long bones and joints. Dev Biol 2007. 310: 304-16.
197. Heberlein, U., Wolff, T., and Rubin, G. M. The TGFbeta homologue dpp and the segment polarity gene hedgehog are required for propagation of a morphogenetic wave in the Drosophilia retina. Cell 1993. 75: 913-926.
198. Laufer, E., Nelson, C. E., Johnson, R. L., Morgan, B. A., and Tabin, C. Sonic hedgehog and FGF-4 act through a signal cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell 1994. 79: 993-1003.
199. Ingham, P. W., and Fietz, M. J. Quantitative effects of hedgehop and decapentaplegic activity on the patterning of the Drosophila wing. Curr Biol 1995. 5: 432-440.
200. Roberts, D. J., Johnson, R. L., Burke, A. C., Nelson, C. E., Morgan, B. A., and Tabin, C. Sonic hedgehog is an endodermal signal inducing Bmp-4 and Hox genes during induction and regionalization of the chick hindgut. Development 1995. 121: 3163-3174.
201. Alvarez, J., Sohn, P., Zeng, X., Doetschman, T., Robbins, D.J., and Serra, R. TGFbeta2 mediates the effects of hedgehog on hypertrophic differentiation and PTHrP expression. Development 2002. 129:1913-24.
202. Mak, K.K., Chen, M.H., Day, T.F., Chuang, P.T., and Yang, Y. Wnt/beta-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation. Development 2006. 133: 3695-707.
203. Niedermaier, M., Schwabe, G.C., Fees, S., Helmrich, A., Brieske, N., Seemann, P., Hecht, J., Seitz, V., Stricker, S., Leschik, G., et al. An inversion involving the mouse Shh locus results in brachydactyly through dysregulation of Shh expression. J Clin Invest 2005. 115: 900-9.
204. Mercader, N., Leonardo, E., Piedra, M.E., Martinez-A, C., Ros, M.A., and Torres, M. Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes. Development 2000. 127: 3961–3970.
205. Casanova, J.C., and Sanz-Ezquerro, J.J. Digit morphogenesis: is the tip different? Dev Growth Differ 2007. 49: 479-91.
206. Niswander, L., Jeffrey, S., Martin, G. R., and Tickle, C. A positive feedback loop coordinates growth and patterning in the vertebrate limb. Nature 1994. 371: 609–612.
207. Sanz-Ezquerro, J.J., and Tickle, C. Fgf signaling controls the number ofphalanges and tip formation in developing digits. Curr Biol 2003. 13: 1830-6.
208. Lewandoski, M., Sun, X., and Martin, G.R. Fgf8 signalling from the AER is essential for normal limb development. Nat Genet 2000. 26: 460-3.
2. Bell, J. On brachydactyly and symphalangism. In: Penrose, L. S.: Treasury of Human Inheritance. London: Cambridge Univ. Press (pub.) 5 1951. Pp. 1-31.
3. http://www.peds.ufl.edu/PEDS2/divisions/genetics/caw/resources_other_malfor mations.htm
4. http://en.wikipedia.org/wiki/William_Curtis_Farabee
5. Farabee, W. C. Hereditary and sexual influence in meristic variation: a study of digital malformations in man. Ph.D. Thesis: Harvard Univ. (pub.) 1903.
6. Drinkwater, H. A second brachydactylous family. J Genet 1914; 4: 323-339.
7. Drinkwater, H. An account of a brachydactylous family. Proc Royal Soc Edin 1908; 28: 35-57.
8. Drinkwater, H. Account of a family showing minor-brachydactyly. J Genet 1912; 2: 21-40.
9. Yang, X.P., She, C.W., Guo, J.Z. et al. A locus for brachydactyly type A-1 maps to chromosome 2q35-q36. Am J Hum Genet 2000; 66: 892-903.
10. Gao, B., Guo, J.Z., She, C.W. et al. Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1. Nat Genet 2001; 28: 386-388.
11. McCready, M.E., Sweeney, E., Fryer, A.E. et al. A novel mutation in the IHH gene causes brachydactyly type A1: a 95-year-old mystery resolved. Hum Genet 2002; 111: 368–375.
12.McCready, M.E., Grimsey, A., Styer, T. et al. A century later Farabee has his mutation. Hum Genet 2005; 117(2-3): 285-7.
13. Kirkpatrick, T.J., Au, K.S., Mastrobattista, J.M. et al. Identification of a mutation in the Indian Hedgehog (IHH) gene causing brachydactyly type A1 and evidence for a third locus. J Med Genet 2003; 40(1): 42-4.
14. Giordano, N., Gennari, L., Bruttini, M. et al. Mild brachydactyly type A1 maps to chromosome 2q35-q36 and is caused by a novel IHH mutation in a three generation family. J Med Genet 2003; 40(2): 132-5.
15. Hellemans, J., Coucke, P.J., Giedion, A. et al. Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. Am J Hum Genet 2003; 72(4): 1040-6.
16. Liu, M.G., Wang, X., Cai, Z. et al. A novel heterozygous mutation in the Indian hedgehog gene (IHH) is associated with brachydactyly type A1 in a Chinese family. J Hum Genet 2006; 51: 727–731.
17. http://www.med.unc.edu/embryo_images/
18. Niswander, L. Pattern formation: old models out on a limb. Nat Rev Genet 2003; 4: 133-43. Review.
19. Saunders, J. W. Jr. The proximo-distal sequence of origin of the parts of the chick wing and the role of the ectoderm. J Exp Zool 1948; 108: 363–403.
20. Summerbell, D. A quantitative analysis of the effect of excision of the AER from the chick limb-bud. J Embryol Exp Morphol 1974; 32: 651–660.
21. Ahn, K. et al. BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal/ventral patterning of the limb. Development 2001; 128: 4449–4461.
22. Pizette, S., Abate-Shen, C. & Niswander, L. BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb. Development 2001; 128: 4463–4474.
23. Kawakami, Y. et al. WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo. Cell 2001; 104: 891–900.
24. Min, H. et al. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev 1998; 12: 3156–3161.
25. Sekine, K. et al. Fgf10 is essential for limb and lung formation. Nature Genet 1999; 21: 138–141.
26. Altabef, M., Clarke, J. D. W. & Tickle, C. Dorso-ventral ectodermal compartments and origin of apical ectodermal ridge in developing chick limb. Development 1997; 124: 4547–4556.
27. Kimmel, R. A. et al. Two lineage boundaries coordinate vertebrate apical ectodermal ridge formation. Genes Dev 2000; 14: 1377–1389.
28.Rubin, L. and Saunders, J. W. J. Ectodermal-mesodermal interactions in the growth of limb buds in the chick embryo: constancy and temporal limits of the ectodermal induction. Dev Biol 1972; 28: 94–112.
29. Niswander, L. et al. FGF-4 replaces the apical ectodermal ridge and direct outgrowth and patterning of the limb. Cell 1993; 75: 579–587.
30. Fallon, J. F. et al. FGF-2: apical ectodermal ridge growth signal for chick limb development. Science 1994; 264: 104–107.
31. Sun, X., Mariani, F. V. & Martin, G. R. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature 2002; 418: 501–508.
32. Pizette, S. & Niswander, L. BMPs negatively regulate structure and function of the limb apical ectodermal ridge. Development 1999; 126: 883–894.
33. Saunders, J. W. Jr & Gasseling, M. T. in Epithelial-Mesenchymal Interactions (eds Fleischmajer, R. & Billingham, R. E.) 78-97 (Williams and Wilkins, Baltimore, 1968).
34. Tickle, C. The number of polarizing region cells required to specify additional digits in the developing chick wing. Nature 1981; 289: 295–298.
35. Tickle, C. et al. Local application of retinoic acid to the limb bud mimics the action of the polarizing region. Nature 1982; 296: 564–565.
36. Helms, J., Thaller, C. and Eichele, G. Relationship between retinoic acid and sonic hedgehog, two polarizing signals in the chick wing bud. Development 1994; 120: 3267–3274.
37. Helms, J. A. et al. Retinoic acid signaling is required during early chick limbdevelopment. Development 1996; 122: 1385–1394 .
38. Stratford, T., Horton, C. & Maden, M. Retinoic acid is required for the initiation of outgrowth in the chick limb bud. Curr Biol 1996; 6: 1124–1133.
39. Lu, H.C. et al. Retinoid signaling is required for the establishment of a ZPA and for the expression of Hoxb-8, a mediator of ZPA formation. Development 1997; 124: 1643–1651.
40. Niederreither, K. et al. Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse. Development 2002; 129: 3563–3574.
41. Riddle, R. D. et al. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 1993; 75: 1401–1416.
42. Chiang, C. et al. Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. Dev Biol 2001; 236: 421–435.
43. Kraus, P., Fraidenraich, D. and Loomis, C. A. Some distal limb structures develop in mice lacking Sonic Hedgehog signaling. Mech Dev 2001; 100: 45–58.
44. Sanz-Ezquerro JJ and Tickle C. Digital development and morphogenesis. J Anat 2003; 202: 51-8.
45. Smith, J.C., Tickle, C. and Wolpert, L. Attenuation of positional signalling in the chicklimb by high doses of gamma radiation. Nature 1978; 272: 612–613.
46. Smith, J. The time required for positional signalling in the chick wing bud. J Embryol Exp Morph 1980; 60: 321–328.
47. Tickle, C. The number of polarizing region cells required to specify additional digits in the developing chick wing. Nature 1981; 289: 295–298.
48. Lee, J. and Tickle, C. Retinoic acid and pattern formation in the developing chick wing. SEM and quantitative studies of early effects on the apical ectodermal ridge and bud outgrowth. J Embryol Exp Morph 1985; 90: 139–169.
49. Brickell, P.M. and Tickle, C. Morphogens in chick limb development. Bioessays 1989; 11: 145–149.
50. Vargesson, N., Clarke, J.D.W., Vincent, K., Coles, C., Wolpert, L. and Tickle, C. Cell fate in the chick limb bud and relationship to gene expression. Development 1997; 124: 1909–1918.
51. Dahn, R.D. and Fallon, J.F. Interdigital regulation of digit identity and homeotic transformation by modulated BMP signaling. Science 2000; 289: 438–441.
52. Sanz-Ezquerro, J.J. and Tickle, C. Autoregulation of Shh expression and Shh induction of cell death suggest a mechanism for modulating polarising activity during chick limb development. Development 2000; 127: 4811–4823.
53. Ganan, Y. Role of TGF betas and BMPs as signals controlling the position of the digits and the areas of interdigital cell death in the developing chick limb autopod. Development 1996; 122: 2349–2357.
54. Hurle, J.M. and Ganan, Y. Interdigital tissue chondrogenesis induced by surgical removal of the ectoderm in the embryonic chick leg bud. J Embryol Exp Morph 1986; 94: 231–244.
55. Omi, M., Sato-Maeda, M. and Ide, H. Role of chondrogenic tissue in programmed cell death and BMP expression in chick limb buds. Int J Dev Biol 2000; 44: 381–388.
56. Cecconi, F., Alvarez-Bolado, G., Meyer, B.I., Roth, K.A. and Gruss, P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 1998; 94: 727–737.
57. Lindsten, T., Ross, A.J., King, A., Zong, W.X., Rathmell, J.C., Shiels, H.A., et al. The combined functions of proapoptic Bc1–2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 2000; 6: 1389–1399.
58. Francis-West, P.H., Parish, J., Lee, K. and Archer, C.W. BMP/GDF–signalling interactions during synovial joint development. Cell Tissue Res 1999; 296: 111–119.
59. Yokouchi, Y., Sasaki, H., Kuroiwa, A. Homeobox gene expression correlates with the bifurcation process of limb cartilage development. Nature 1991; 353: 443–445.
60. Khoa, N.D., Hasunuma, T., Kobata, T., et al. Expression of murine HOXD9 during embryonic joint patterning and in human T lymphotropic virus type I tax transgenic mice with arthropathy resembling rheumatoid arthritis. Arthr Rheum 1999; 42: 686–696.
61. Fromental-Ramain, C., Warot, X., Messadecq, N., et al. Hoxa-13 and Hod-13 play a crucial role in the patterning of the limb autopod. Development 1996; 122: 2997–3011.
62. Mitrovic, D. Development of the metatarsalphalangeal joint of the chick embryo: Morphological, ultrastructural and histochemical studies. A J Anat 1977; 150: 333–348.
63. Storm, E.E., Kingsley, D.M. GDF5 coordinates bone and joint formation during digit development. Dev Biol 1999; 209: 11–27.
64. Francis-West, P.H., Abdelfattah, A., Chen, P., et al. Mechanisms of GDF-5 action during skeletal development. Development 1999; 126: 1305–1315.
65. Merino, R., Macias, D., Ganan, Y., et al. Expression and function of GDF-5 during digit skeletogenesis in the embryonic chick leg bud. Dev Biol 1999; 206: 33–45.
66. Hartmann, C., Tabin, C.J. Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton. Cell 2001; 104: 341–351.
67. Guo, X., Day, T.F., Jiang, X., Garrett-Beal, L., Topol, L., Yang, Y. Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation. Genes Dev 2004; 18(19): 2404-17.
68. Sp?ter, D., Hill, T.P., O'sullivan, R.J., Gruber, M., Conner, D.A., Hartmann, C. Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis. Development 2006; 133(15): 3039-49.
69. Spagnoli, A., O'Rear, L., Chandler, R.L., Granero-Molto, F., Mortlock, D.P., Gorska, A.E., Weis, J.A., Longobardi, L., Chytil, A., Shimer, K., Moses, H.L. TGF-beta signaling is essential for joint morphogenesis. J Cell Biol 2007; 177(6): 1105-17.
70. Borgens, R.B. Mice regrow the tips of their foretoes. Science 1982; 217: 747–750.
71. Reginelli, A.D., Wang, Y.Q., Sassoon, D., and Muneoka, K. Digit tip regeneration correlates with regions of Msx1 (Hox7) expression in fetal and newborn mice. Development 1995; 121: 1065–1076.
72. Pacifici, M., Liu, M., and Koyama, E. Joint formation: new findings shed more light on this critical process in skeletogenesis. Current Opinion in Orthopaedics 2002; 13: 339–344.
73. Hall, B.K. and Miyake, T. All for one and one for all: condensations and the initiation of skeletal development. BioEsssays 2000; 22: 138–147.
74. Kronenberg, H.M. Developmental regulation of the growth plate. Nature 2003; 423(6937): 332-6.
75. Noonan, K.J., Hunziker, E.B., Nessler, J. and Buckwalter, J.A. Changes in cell, matrix compartment, and fibrillar collagen volumes between growth-plate zones. J Orthop Res 1998; 16: 500–508.
76. St-Jacques, B., Hammerschmidt, M. and McMahon, A.P. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 1999; 13: 2072–2086. [Published erratum appears in Genes Dev 1999; 13: 2617.]
77. Long, F., Zhang, X.M., Karp, S., Yang, Y. and McMahon, A.P. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 2001; 128: 5099–5108.
78. Karaplis, A. C. et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormonerelated peptide gene. Genes Dev 1994; 8: 277–289.
79. Lanske, B. et al. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 1996; 273: 663–666.
80. Weir, E. C. et al. Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation. Proc Natl Acad Sci 1996; 93: 10240–10245.
81. Schipani, E. et al. Targeted expression of constitutively active receptors for parathyroid hormone and parathyroid hormone-related peptide delays endochondral bone formation and rescues mice that lack parathyroid hormone-related peptide. Proc Natl Acad Sci USA 1997; 94: 13689–13694.
82. Karp, S.J. et al. Indian Hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent. Development 2000; 127: 543–548.
83. Vortkamp, A. et al. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH related protein. Science 1996; 273: 613–622.
84. Chung, U.I., Lanske, B., Lee, K., Li, E. and Kronenberg, H. The parathyroid hormone/parathyroid hormone-related peptide receptor coordinates endochondral bone development by directly controlling chondrocyte differentiation. Proc Natl Acad Sci USA 1998; 95: 13030–13035.
85. Chung, U.I., Schipani, E., McMahon, A.P. and Kronenberg, H.M. Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. J Clin Invest 2001; 107: 295–304.
86. Ornitz, D. M. and Marie, P. J. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 2002; 16: 1446–1465.
87. Murakami, S., Kan, M., McKeehan, W. L. and de Crombrugghe, B. Up-regulationof the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. Proc Natl Acad Sci USA 2000; 97: 1113–1118.
88. Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A. and Leder, P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 1996; 84: 911–921.
89. Colvin, J. S., Bohne, B. A., Harding, G. W., McEwen, D. G. and Ornitz, D. M. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genet 1996; 12: 390–397.
90. Naski, M. C., Colvin, J. S., Coffin, J. D. and Ornitz, D. M. Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 1998; 125: 4977–4988.
91. Sahni, M. et al. FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev 1999; 13: 1361–1366.
92. Liu, Z., Xu, J., Colvin, J. S. and Ornitz, D. M. Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev 2002; 16: 859–869.
93. Ohbayashi, N. et al. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev 2002; 16: 870–879.
94. Minina, E., Kreschel, C., Naski, M. C., Ornitz, D. M. and Vortkamp, A. Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev Cell 2002; 3: 439–449.
95. Rosen, V. and Wozney, J. M. in Principles of Bone Biology (eds Bilezikian, J. P.,Raisz, L. G. & Rodan, G. A.) 919–928 (Academic, San Diego, 2002).
96. Pizette, S. and Niswander, L. BMPs are required at two steps of limb chondrogenesis: formation of prechondrogenic condensations and their differentiation into chondrocytes. Dev Biol 2000; 219: 237–249.
97. Brunet, L.J., McMahon, J.A., McMahon, A.P. and Harland, R.M. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 1998; 280: 1455–1458.
98. Kingsley, D.M. et al. The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGF beta superfamily. Cell 1992; 71: 399–410.
99. Yi, S.E., Daluiski, A., Pederson, R., Rosen, V. and Lyons, K. M. The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. Development 2000; 127: 621–630.
100. Baur, S.T., Mai, J.J. and Dymecki, S.M. Combinatorial signaling through BMP receptor IB and GDF5: shaping of the distal mouse limb and the genetics of distal limb diversity. Development 2000; 127: 605–619.
101. Minina, E. et al. BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation anddifferentiation. Development 2001; 128: 4523–4534.
102. Bi, W., Deng, J. M., Zhang, Z., Behringer, R.R. and de Crombrugghe, B. Sox9 is required for cartilage formation. Nature Genet 1999; 22: 85–89.
103. Akiyama, H., Chaboissier, M. C., Martin, J. F., Schedl, A. and de Crombrugghe, B. The transcription factor Sox9 has essential roles in successive steps of thechondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 2002; 16: 2813–2828.
104. Smits, P. et al. The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev Cell 2001; 1: 277–290.
105. Otto, F. et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 1997; 89: 765–771.
106. Komori, T. et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997; 89: 755–764.
107. Inada, M. et al.Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev Dyn 1999; 214: 279–290.
108. Takeda, S., Bonnamy, J.P., Owen, M.J., Ducy, P. and Karsenty, G. Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. Genes Dev 2001; 15: 467–481.
109. Ueta, C. et al. Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J Cell Biol 2001; 153: 87–100.
110. Nusslein-Volhard, C. and Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 1980; 287: 795–801.
111. McMahon, A.P., Ingham, P.W. and Tabin, C.J. Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 2003; 53: 1–114.
112. Chiang C, Litingtung Y, Lee E, et al. Cyclopia and defective axial patterning inmice lacking Sonic hedgehog gene function. Nature, 1996, 383:407–13
113. Bitgood, M.J., McMahon, A.P. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev. Biol. 1995;172: 126-138.
114. Baron, M. H. Embryonic origins of mammalian hematopoiesis. Exp Hematol 2003; 31: 1160–1169.
115. Machold, R. et al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 2003; 39: 937–950.
116. Palma, V. and Ruiz i Altaba, A. Hedgehog–GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development 2004; 131: 337–345.
117. Adolphe, C. et al. An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Development 2004; 131: 5009–5019.
118. Maye, P. et al. Hedgehog signaling is required for the differentiation of ES cells into neurectoderm. Dev Biol 2004; 265: 276–290.
119. Pasca di Magliano, M. and Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nature Rev Cancer 2003; 3: 903–911.
120. Lum, L. and Beachy, P.A. The Hedgehog response network: sensors, switches, and routers. Science 2004; 304: 1755–1759.
121. Lee, J.J., et al. Autoproteolysis in hedgehog protein biogenesis. Science 1994;266: 1528–1537.
122. Bumcrot, D.A., Takata, R., and McMahon, A.P. Proteolytic processing yields two secreted forms of Sonic hedgehog. Mol Cell Biol 1995; 15: 2294–2303.
123. Chu, T., Chiu, M., Zhang, E., Kunes, S. A C-terminal motif targets Hedgehog to axons, coordinating assembly of the Drosophila eye and brain. Dev Cell 2006; 10: 635-646.
124. Miao-Hsueh, Chen., Ya-Jun, Li., Takatoshi, Kawakami., Shan-Mei, Xu. and Pao-Tien, Chuang. Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes & Dev 2004; 18: 641-659
125. Burke, R., Nellen, D., Bellotto, M., Hafen, E., Senti, K.A., Dickson, B.J., Basler, K. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell 1999; 99: 803-815.
126. Lewis, P.M., Dunn, M.P., McMahon, J.A., Logan, M., Martin, J.F., St-Jacques, B., McMahon, A.P. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 2001; 105: 599-612.
127. Yina, Li., Huimin, Zhang., Ying, Litingtung., and Chin, Chiang. Cholesterol modification restricts the spread of Shh gradient in the limb bud. Proc Natl Acad Sci USA 2006; 103: 6548–6553.
128. Panakova, D., Sprong, H., Marois, E., Thiele, C., Eaton, S. Lipoprotein particles are required for Hedgehog and Wingless signalling. Nature 2005; 435: 58-65.
129. Tanaka, Y., Okada, Y., Hirokawa, N. FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination. Nature 2005; 435: 172-177.
130. http://upload.wikimedia.org/wikipedia/commons/archive/5/55/20070124120537!Shh_processing.png
131. Rohatgi, R., Scott, M.P. Patching the gaps in Hedgehog signalling. Nat Cell Biol 2007; 9(9): 1005-1009.
132. Chen, Y., Struhl, G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 1996; 87(3): 553-63.
133. Chuang, P.T., McMahon, A.P. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999; 397(6720): 617-21.
134. Tenzen, T., Allen, B.L., Cole, F., Kang, J.S., Krauss, R.S., McMahon, A.P. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell 2006; 10: 647-656.
135. Yao, S., Lum, L., Beachy, P. The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell 2006; 125: 343-357.
136. Zhang, W., Kang, J.S., Cole, F., Yi, M.J., Krauss, R.S. Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev Cell 2006; 10: 657-665.
137. Takei, Y., Ozawa, Y., Sato, M., Watanabe, A., Tabata, T. Three Drosophila EXTgenes shape morphogen gradients through synthesis of heparan sulfate proteoglycans. Development 2004; 131: 73–82.
138. Bornemann, D.J., Duncan, J.E., Staatz, W., Selleck, S., Warrior, R.. Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways. Development 2004; 131: 1927–1938.
139. Koziel, L., Kunath, M., Kelly, O.G., Vortkamp, A. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell 2004; 6: 801–813.
140. Glise, B., Miller, C.A., Crozatier, M., Halbisen, M.A., Wise, S., Olson, D.J., Vincent, A., Blair, S.S. Shifted, the Drosophila ortholog of Wnt inhibitory factor-1, controls the distribution and movement of Hedgehog. Dev Cell 2005; 8: 255-266.
141. Gorfinkiel, N., Sierra, J., Callejo, A., Ibanez, C., Guerrero, I. The Drosophila ortholog of the human Wnt inhibitor factor Shifted controls the diffusion of lipid-modified Hedgehog. Dev Cell 2005; 8: 241-253.
142. Hollway, G.E., Maule, J., Gautier, P., Evans, T.M., Keenan, D.G., Lohs, C., Fischer, D., Wicking, C., Currie, P.D. Scube2 mediates Hedgehog signalling in the zebrafish embryo. Dev Biol 2006; 294: 104-118.
143. Kawakami, A., Nojima, Y., Toyoda, A., Takahoko, M., Satoh, M., Tanaka, H., Wada, H., Masai, I., Terasaki, H., Sakaki, Y. et al. The zebrafish-secreted matrix protein you/scube2 is implicated in long-range regulation of hedgehog signaling. Curr Biol 2005; 15: 480-488.
144. Woods, I.G., Talbot, W.S. The you gene encodes an EGF-CUB protein essential for Hedgehog signaling in zebrafish. PLoS Biol 2005; 3: e66.
145. Reiter, J.F., Skarnes, W.C. Tectonic, a novel regulator of the Hedgehog pathway required for both activation and inhibition. Genes Dev 2006; 20: 22-27.
146. Chen, J.K., Taipale, J., Cooper, M.K., Beachy, P.A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002; 16: 2743-2748.
147. Sinha, S., Chen, J.K. Purmorphamine activates the Hedgehog pathway by targeting Smoothened. Nat Chem Biol 2006; 2: 29-30.
148. Bijlsma, M.F., Spek, C.A., Zivkovic, D., van de Water, S., Rezaee, F., Peppelenbosch, M.P. Repression of Smoothened by patcheddependent (pro-)vitamin D3 secretion. PLoS Biol 2006; 4: e232.
149. Corcoran, R.B., Scott, M.P. Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci USA 2006; 103: 8408-8413.
150. Stegman, M. A. et al. The Kinesin-related protein Costal2 associates with membranes in a Hedgehog-sensitive, Smoothened-independent manner. J Biol Chem 2004; 279: 7064–7071.
151. Robbins, D.J. et al. Hedgehog elicits signal transduction by means of a large complex containing the kinesinrelated protein costal2. Cell 1997; 90: 225–234.
152. Sisson, J.C., Ho, K.S., Suyama, K. and Scott, M.P. Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway. Cell 1997; 90: 235–245.
153. Zhang, W. et al. Hedgehog-regulated costal2-kinase complexes control phosphorylation and proteolytic processing of cubitus interruptus. Dev Cell 2005; 8: 267–278.
154. Jiang, J. and Struhl, G. Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 1998; 391: 493–496.
155. Dai, P., Akimaru, H., and Ishii, S. A hedgehog-responsive region in the Drosophila wing disc is defined by debramediated ubiquitination and lysosomal degradation of Ci. Dev Cell 2003; 4: 917–928.
156. Lum, L. et al. Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2. Mol Cell 2003; 12: 1261–1274.
157. Methot, N. and Basler, K. Suppressor of Fused opposes Hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development 2000; 127: 4001–4210.
158. Cheng, S.Y. and Bishop, J.M. Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18–mSin3 corepressor complex. Proc Natl Acad Sci USA 2002; 99: 5442–5447.
159. Merchant, M. et al. Suppressor of fused regulates Gli activity through a dual binding mechanism. Mol Cell Biol 2004; 24: 8627–8641.
160. Jia, J., Tong, C., Wang, B., Luo, L. and Jiang, J. Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase 1. Nature 2005; 432: 1045–1050.
161. Apionishev, S., Katanayeva, N.M., Marks, S.A., Kalderon, D. and Tomlinson, A. Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Nature Cell Biol 2005; 7: 86–92.
162. Zhang, C., Williams, E. H., Guo, Y., Lum, L. and Beachy, P. A. Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc Natl Acad Sci USA 2004; 101: 17900–17907.
163. Stegman, M.A. et al. Identification of a tetrameric hedgehog signaling complex. J Biol Chem 2000; 275: 21809–21812.
164. Rahnama, F., Toftgard, R. and Zaphiropoulos, P.G. Distinct roles of PTCH2 splice variants in Hedgehog signalling. Biochem. J. 2004; 378: 325–334.
165. Tay, S.Y., Ingham, P.W., Roy, S. A homologue of the Drosophila kinesin-like protein Costal2 regulates Hedgehog signal transduction in the vertebrate embryo. Development 2005; 132: 625-634.
166. Varjosalo, M., Li, S.P., Taipale, J. Divergence of hedgehog signal transduction mechanism between Drosophila and mammals. Dev Cell 2006; 10: 177-186.
167. Corbit, K.C., Aanstad, P., Singla, V., Norman, A.R., Stainier, D.Y., Reiter, J.F. Vertebrate Smoothened functions at the primary cilium. Nature 2005; 437: 1018-1021.
168. Haycraft, C.J., Banizs, B., Aydin-Son, Y., Zhang, Q., Michaud, E.J., Yoder, B.K. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 2005; 1: e53.
169. Huangfu, D., Anderson, K.V. Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci USA 2005; 102: 11325-11330.
170. Huangfu, D., Liu, A., Rakeman, A.S., Murcia, N.S., Niswander, L., Anderson, K.V. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 2003; 426: 83-87.
171. Liu, A., Wang, B., Niswander, L.A. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development 2005; 132: 3103-3111.
172. Cooper, A.F., Yu, K.P., Brueckner, M., Brailey, L.L., Johnson, L., McGrath, J.M., Bale, A.E. Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Development 2005; 132: 4407-4417.
173. Koudijs, M.J., den Broeder, M.J., Keijser, A., Wienholds, E., Houwing, S., van Rooijen, E.M., Geisler, R., van Eeden, F.J. The zebrafish mutants dre, uki, and lep encode negative regulators of the hedgehog signaling pathway. PLoS Genet 2005; 1: e19.
174. Svard, J., Heby-Henricson, K., Persson-Lek, M., Rozell, B., Lauth, M., Bergstrom, A., Ericson, J., Toftgard, R., Teglund, S. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell 2006; 10: 187-197.
175. Preat, T., Therond, P., Limbourg-Bouchon, B., Pham, A., Tricoire, H., Busson, D., Lamour-Isnard, C. Segmental polarity in Drosophila melanogaster: genetic dissection of fused in a Suppressor of fused background reveals interaction with costal-2. Genetics 1993; 135: 1047-1062.
176. Chen, M.H., Gao, N., Kawakami, T., Chuang, P.T. Mice deficient in the fused homolog do not exhibit phenotypes indicative of perturbed hedgehog signaling during embryonic development. Mol Cell Biol 2005; 25: 7042-7053.
177. Merchant, M., Evangelista, M., Luoh, S.M., Frantz, G.D., Chalasani, S., Carano, R.A., van Hoy, M., Ramirez, J., Ogasawara, A.K., McFarland, L.M. et al. Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol Cell Biol 2005; 25: 7054-7068.
178. Wolff, C., Roy, S., Ingham, P.W. Multiple muscle cell identities induced by distinct levels and timing of hedgehog activity in the zebrafish embryo. Curr Biol 2003; 13: 1169-1181.
179. Karlstrom, R.O., Tyurina, O.V., Kawakami, A., Nishioka, N., Talbot, W.S., Sasaki, H., Schier, A.F. Genetic analysis of zebrafish gli1 and gli2 reveals divergent requirements for gli genes in vertebrate development. Development 2003; 130: 1549-1564.
180. Zhang, W., Zhao, Y., Tong, C., Wang, G., Wang, B., Jia, J., Jiang, J. Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Dev Cell 2005; 8: 267-278.
181. Jia, J., Zhang, L., Zhang, Q., Tong, C., Wang, B., Hou, F., Amanai, K., Jiang, J. Phosphorylation by double-time/CKIe and CKIa targets cubitus interruptus for Slimb/b-TRCP-mediated proteolytic processing. Dev Cell 2005; 9: 819-830.
182. Smelkinson, M.G., Kalderon, D. Processing of the Drosophila hedgehog signaling effector Ci-155 to the repressor Ci-75 is mediated by direct binding to the SCF component Slimb. Curr Biol 2006; 16: 110-116.
183. Tempe, D., Casas, M., Karaz, S., Blanchet-Tournier, M.F., Concordet, J.P. Multisite protein kinase A and glycogen synthase kinase 3b phosphorylation leads to Gli3 ubiquitination by SCF?TrCP. Mol Cell Biol 2006; 26: 4316-4326.
184. Wang, B., Li, Y. Evidence for the direct involvement of bTrCP in Gli3 protein processing. Proc Natl Acad Sci USA 2006; 103: 33-38.
185. Pan, Y., Bai, C.B., Joyner, A.L., Wang, B. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol 2006; 26: 3365-3377.
186. Huntzicker, E.G., Estay, I.S., Zhen, H., Lokteva, L.A., Jackson, P.K., Oro, A.E. Dual degradation signals control Gli protein stability and tumor formation. Genes Dev 2006; 20: 276-281.
187. Zhang, Q., Zhang, L., Wang, B., Ou, C.Y., Chien, C.T., Jiang, J. A hedgehog-induced BTB protein modulates hedgehog signaling by degrading Ci/Gli transcription factor. Dev Cell 2006; 10: 719-729.
188. Riobo, N.A., Lu, K., Ai, X., Haines, G.M., Emerson, C.P.Jr. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc Natl Acad Sci USA 2006; 103: 4505-4510.
189. Davey MG, Paton IR, Yin Y, Schmidt M, Bangs FK, Morrice DR, Smith TG, Buxton P, Stamataki D, Tanaka M et al. The chicken talpid3 gene encodes a novel protein essential for Hedgehog signaling. Genes Dev 2006; 20: 1365-1377.
190. Hooper, J.E., Scott, M.P. Communicating with Hedgehogs. Nat Rev Mol Cell Biol 2005; 6(4): 306-17.
191. Bo Gao. Developmental Genetics of the Distal Skeletal Elements of Limbs in Vertebrate Based on Brachydactyly Type A1 (BDA1). Dissertation 2005; SJTU.
192. Haaf, T. High-resolution analysis of DNA replication in released chromatin fibers containing 5-bromodeoxyuridine. Biotechniques 1996; 21: 1050-4.
193. Schmahl, J., Eicher, E.M., Washburn, L.L., and Capel, B. Sry induces cell proliferation in the mouse gonad. Development 2000. 127: 65-73.
194. Basler, K., and Struhl, G. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 1994. 368: 208-14.
195. Tabata, T., and Kornberg, T.B. Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell 1994. 76: 89-102.
196. Seo, H.S., and Serra, R. Deletion of Tgfbr2 in Prx1-cre expressing mesenchyme results in defects in development of the long bones and joints. Dev Biol 2007. 310: 304-16.
197. Heberlein, U., Wolff, T., and Rubin, G. M. The TGFbeta homologue dpp and the segment polarity gene hedgehog are required for propagation of a morphogenetic wave in the Drosophilia retina. Cell 1993. 75: 913-926.
198. Laufer, E., Nelson, C. E., Johnson, R. L., Morgan, B. A., and Tabin, C. Sonic hedgehog and FGF-4 act through a signal cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell 1994. 79: 993-1003.
199. Ingham, P. W., and Fietz, M. J. Quantitative effects of hedgehop and decapentaplegic activity on the patterning of the Drosophila wing. Curr Biol 1995. 5: 432-440.
200. Roberts, D. J., Johnson, R. L., Burke, A. C., Nelson, C. E., Morgan, B. A., and Tabin, C. Sonic hedgehog is an endodermal signal inducing Bmp-4 and Hox genes during induction and regionalization of the chick hindgut. Development 1995. 121: 3163-3174.
201. Alvarez, J., Sohn, P., Zeng, X., Doetschman, T., Robbins, D.J., and Serra, R. TGFbeta2 mediates the effects of hedgehog on hypertrophic differentiation and PTHrP expression. Development 2002. 129:1913-24.
202. Mak, K.K., Chen, M.H., Day, T.F., Chuang, P.T., and Yang, Y. Wnt/beta-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation. Development 2006. 133: 3695-707.
203. Niedermaier, M., Schwabe, G.C., Fees, S., Helmrich, A., Brieske, N., Seemann, P., Hecht, J., Seitz, V., Stricker, S., Leschik, G., et al. An inversion involving the mouse Shh locus results in brachydactyly through dysregulation of Shh expression. J Clin Invest 2005. 115: 900-9.
204. Mercader, N., Leonardo, E., Piedra, M.E., Martinez-A, C., Ros, M.A., and Torres, M. Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes. Development 2000. 127: 3961–3970.
205. Casanova, J.C., and Sanz-Ezquerro, J.J. Digit morphogenesis: is the tip different? Dev Growth Differ 2007. 49: 479-91.
206. Niswander, L., Jeffrey, S., Martin, G. R., and Tickle, C. A positive feedback loop coordinates growth and patterning in the vertebrate limb. Nature 1994. 371: 609–612.
207. Sanz-Ezquerro, J.J., and Tickle, C. Fgf signaling controls the number ofphalanges and tip formation in developing digits. Curr Biol 2003. 13: 1830-6.
208. Lewandoski, M., Sun, X., and Martin, G.R. Fgf8 signalling from the AER is essential for normal limb development. Nat Genet 2000. 26: 460-3.
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