Advertisement

Animal Models of Idiopathic Scoliosis

  • Zhaoyang Liu
  • Ryan Scott Gray
Chapter

Abstract

Structural deformity of the spine can present during embryonic development as well as during a range of postnatal growth and maturation in humans. The most common spine disorders observed in human are classified as idiopathic scoliosis (IS), with the majority of these presenting during adolescence. By definition there is a limited understanding of the underlying causes of these idiopathic disorders. Several animal models have been reported to display hallmarks and characteristic traits of IS ranging from pineal gland resection in chicken to surgically induced scoliosis in large animal models to more recent examples of heritable genetic models in mouse and zebrafish. Moreover, recent progress using human genomic studies coupled with genetically tractable models of IS using the mouse and zebrafish has begun to advance a more mechanistic understanding of the genetics and pathogenesis of this condition. In this chapter, we review the range of animal models for IS, highlighting the important findings from each model and addressing caveats for consideration. Studies using relevant animal models have tremendous potential to identify the mechanisms underlying IS and other diseases of the spine and offer an ethical and cost-effective platform for the development of novel therapeutics.

Notes

Acknowledgments

The authors would like to acknowledge Roberto Gonzalez for zebrafish histology and Drs. Michel Bagnat, Christina Gurnett, and Gabriel Haller for critical discussion of this manuscript. This work was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR072009).

References

  1. 1.
    Smith LJ, Nerurkar NL, Choi KS, Harfe BD, Elliott DM. Degeneration and regeneration of the intervertebral disc: lessons from development. Dis Model Mech. 2011;4(1):31–41.PubMedCrossRefGoogle Scholar
  2. 2.
    Eckalbar WL, Fisher RE, Rawls A, Kusumi K. Scoliosis and segmentation defects of the vertebrae. Wiley Interdiscip Rev Dev Biol. 2012;1(3):401–23.PubMedCrossRefGoogle Scholar
  3. 3.
    Koehl MA, Quillin KJ, Pell CA. Mechanical design of fiber-wound hydraulic skeletons: the stiffening and straightening of embryonic notochords. Am Zool. 2000;40:28–41.Google Scholar
  4. 4.
    Adams DS, Keller R, Koehl MA. The mechanics of notochord elongation, straightening and stiffening in the embryo of Xenopus laevis. Development. 1990;110(1):115–30.PubMedGoogle Scholar
  5. 5.
    Glickman NS, Kimmel CB, Jones MA, Adams RJ. Shaping the zebrafish notochord. Development. 2003;130(5):873–87.PubMedCrossRefGoogle Scholar
  6. 6.
    Shapiro IM, Risbud MV. Introduction to the structure, function, and comparative anatomy of the vertebrae and the intervertebral disc. In: Shapiro IM, Risbud MV, editors. The intervertebral disc: molecular and structural studies of the disc in health and disease. Vienna: Springer; 2014. p. 3–15.CrossRefGoogle Scholar
  7. 7.
    Choi KS, Cohn MJ, Harfe BD. Identification of nucleus pulposus precursor cells and notochordal remnants in the mouse: implications for disk degeneration and chordoma formation. Dev Dyn. 2008;237(12):3953–8.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Newton Ede MM, Jones SW. Adolescent idiopathic scoliosis: evidence for intrinsic factors driving aetiology and progression. Int Orthop. 2016;40(10):2075–80.PubMedCrossRefGoogle Scholar
  9. 9.
    Jackson HC 2nd, Winkelmann RK, Bickel WH. Nerve endings in the human lumbar spinal column and related structures. J Bone Joint Surg Am. 1966;48(7):1272–81.PubMedCrossRefGoogle Scholar
  10. 10.
    Kojima Y, Maeda T, Arai R, Shichikawa K. Nerve supply to the posterior longitudinal ligament and the intervertebral disc of the rat vertebral column as studied by acetylcholinesterase histochemistry. I. Distribution in the lumbar region. J Anat. 1990;169:237–46.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Man GC, Wang WW, Yim AP, Wong JH, Ng TB, Lam TP, et al. A review of pinealectomy-induced melatonin-deficient animal models for the study of etiopathogenesis of adolescent idiopathic scoliosis. Int J Mol Sci. 2014;15(9):16484–99.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Lombardi G, Akoume MY, Colombini A, Moreau A, Banfi G. Biochemistry of adolescent idiopathic scoliosis. Adv Clin Chem. 2011;54:165–82.PubMedCrossRefGoogle Scholar
  13. 13.
    Normand E, Franco A, Moreau A, Marcil V. Dipeptidyl Peptidase-4 and adolescent idiopathic scoliosis: expression in osteoblasts. Sci Rep. 2017;7(1):3173.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Blecher R, Krief S, Galili T, Biton IE, Stern T, Assaraf E, et al. The proprioceptive system masterminds spinal alignment: insight into the mechanism of scoliosis. Dev Cell. 2017;42(4):388–99. e3PubMedCrossRefGoogle Scholar
  15. 15.
    Pourquie O. Vertebrate segmentation: from cyclic gene networks to scoliosis. Cell. 2011;145(5):650–63.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Giampietro PF, Dunwoodie SL, Kusumi K, Pourquie O, Tassy O, Offiah AC, et al. Progress in the understanding of the genetic etiology of vertebral segmentation disorders in humans. Ann N Y Acad Sci. 2009;1151:38–67.PubMedCrossRefGoogle Scholar
  17. 17.
    Sparrow DB, Chapman G, Dunwoodie SL. The mouse notches up another success: understanding the causes of human vertebral malformation. Mamm Genome. 2011;22(7–8):362–76.PubMedCrossRefGoogle Scholar
  18. 18.
    Gansner JM, Mendelsohn BA, Hultman KA, Johnson SL, Gitlin JD. Essential role of lysyl oxidases in notochord development. Dev Biol. 2007;307(2):202–13.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Gansner JM, Gitlin JD. Essential role for the alpha 1 chain of type VIII collagen in zebrafish notochord formation. Dev Dyn. 2008;237(12):3715–26.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Christiansen HE, Lang MR, Pace JM, Parichy DM. Critical early roles for col27a1a and col27a1b in zebrafish notochord morphogenesis, vertebral mineralization and post-embryonic axial growth. PLoS One. 2009;4(12):e8481.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Gray RS, Wilm TP, Smith J, Bagnat M, Dale RM, Topczewski J, et al. Loss of col8a1a function during zebrafish embryogenesis results in congenital vertebral malformations. Dev Biol. 2014;386(1):72–85.PubMedCrossRefGoogle Scholar
  22. 22.
    Ellis K, Bagwell J, Bagnat M. Notochord vacuoles are lysosome-related organelles that function in axis and spine morphogenesis. J Cell Biol. 2013;200(5):667–79.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Sparrow DB, Chapman G, Smith AJ, Mattar MZ, Major JA, O'Reilly VC, et al. A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell. 2012;149(2):295–306.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Purkiss SB, Driscoll B, Cole WG, Alman B. Idiopathic scoliosis in families of children with congenital scoliosis. Clin Orthop Relat Res. 2002;401:27–31.CrossRefGoogle Scholar
  25. 25.
    Guo L, Yamashita H, Kou I, Takimoto A, Meguro-Horike M, Horike S, et al. Functional investigation of a non-coding variant associated with adolescent idiopathic scoliosis in zebrafish: elevated expression of the ladybird Homeobox gene causes body Axis deformation. PLoS Genet. 2016;12(1):e1005802.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Hayes M, Gao X, Yu LX, Paria N, Henkelman RM, Wise CA, et al. ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease. Nat Commun. 2014;5:4777.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    McGreevy JW, Hakim CH, McIntosh MA, Duan D. Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy. Dis Model Mech. 2015;8(3):195–213.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Harrison DJ, Webb PJ. Scoliosis in the Rett syndrome: natural history and treatment. Brain and Development. 1990;12(1):154–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Taylor LJ. Severe spondylolisthesis and scoliosis in association with Marfan’s syndrome. Case report and review of the literature. Clin Orthop Relat Res. 1987;221:207–11.Google Scholar
  30. 30.
    Shirley ED, Demaio M, Bodurtha J. Ehlers-danlos syndrome in orthopaedics: etiology, diagnosis, and treatment implications. Sports Health. 2012;4(5):394–403.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Blanco G, Coulton GR, Biggin A, Grainge C, Moss J, Barrett M, et al. The kyphoscoliosis (ky) mouse is deficient in hypertrophic responses and is caused by a mutation in a novel muscle-specific protein. Hum Mol Genet. 2001;10(1):9–16.PubMedCrossRefGoogle Scholar
  32. 32.
    Chen F, Guo R, Itoh S, Moreno L, Rosenthal E, Zappitelli T, et al. First mouse model for combined osteogenesis imperfecta and Ehlers-Danlos syndrome. J Bone Miner Res. 2014;29(6):1412–23.PubMedCrossRefGoogle Scholar
  33. 33.
    Haller G, Alvarado D, McCall K, Yang P, Cruchaga C, Harms M, et al. A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis. Hum Mol Genet. 2016;25(1):202–9.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Buchan JG, Alvarado DM, Haller GE, Cruchaga C, Harms MB, Zhang T, et al. Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis. Hum Mol Genet. 2014;23(19):5271–82.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Cheng JC, Castelein RM, Chu WC, Danielsson AJ, Dobbs MB, Grivas TB, et al. Adolescent idiopathic scoliosis. Nat Rev Dis Primers. 2015;1:15030.PubMedCrossRefGoogle Scholar
  36. 36.
    van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, O'Collins V, et al. Can animal models of disease reliably inform human studies? PLoS Med. 2010;7(3):e1000245.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    McGonigle P, Ruggeri B. Animal models of human disease: challenges in enabling translation. Biochem Pharmacol. 2014;87(1):162–71.PubMedCrossRefGoogle Scholar
  38. 38.
    Boszczyk BM, Boszczyk AA, Putz R. Comparative and functional anatomy of the mammalian lumbar spine. Anat Rec. 2001;264(2):157–68.PubMedCrossRefGoogle Scholar
  39. 39.
    Langenskiold A, Michelsson JE. Experimental progressive scoliosis in the rabbit. J Bone Joint Surg Br. 1961;43-B:116–20.PubMedCrossRefGoogle Scholar
  40. 40.
    Langenskiold A, Michelsson JE. Experimental scoliosis. Acta Orthop Scand. 1959;29:158–9.PubMedGoogle Scholar
  41. 41.
    Langenskiold A, Michelsson JE. The pathogenesis of experimental progressive scoliosis. Acta Orthop Scand Suppl. 1962;59:1–26.PubMedGoogle Scholar
  42. 42.
    Kubota K, Doi T, Murata M, Kobayakawa K, Matsumoto Y, Harimaya K, et al. Disturbance of rib cage development causes progressive thoracic scoliosis: the creation of a nonsurgical structural scoliosis model in mice. J Bone Joint Surg Am. 2013;95(18):e130.PubMedCrossRefGoogle Scholar
  43. 43.
    Stokes IA, Laible JP. Three-dimensional osseo-ligamentous model of the thorax representing initiation of scoliosis by asymmetric growth. J Biomech. 1990;23(6):589–95.PubMedCrossRefGoogle Scholar
  44. 44.
    Andriacchi T, Schultz A, Belytschko T, Galante J. A model for studies of mechanical interactions between the human spine and rib cage. J Biomech. 1974;7(6):497–507.PubMedCrossRefGoogle Scholar
  45. 45.
    Grivas TB, Burwell RG, Purdue M, Webb JK, Moulton A. A segmental analysis of thoracic shape in chest radiographs of children. Changes related to spinal level, age, sex, side and significance for lung growth and scoliosis. J Anat. 1991;178:21–38.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Gurnett CA, Alaee F, Bowcock A, Kruse L, Lenke LG, Bridwell KH, et al. Genetic linkage localizes an adolescent idiopathic scoliosis and pectus excavatum gene to chromosome 18 q. Spine. 2009;34(2):E94–100.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Hong JY, Suh SW, Park HJ, Kim YH, Park JH, Park SY. Correlations of adolescent idiopathic scoliosis and pectus excavatum. J Pediatr Orthop. 2011;31(8):870–4.PubMedCrossRefGoogle Scholar
  48. 48.
    Dubousset J, Wicart P, Pomero V, Barois A, Estournet B. Spinal penetration index: new three-dimensional quantified reference for lordoscoliosis and other spinal deformities. J Orthop Sci. 2003;8(1):41–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Doi T, Harimaya K, Matsumoto Y, Iwamoto Y. Aortic location and flat chest in scoliosis: a prospective study. Fukuoka Igaku Zasshi. 2011;102(1):14–9.PubMedGoogle Scholar
  50. 50.
    Ilharreborde B, Dubousset J, Le Huec JC. Use of EOS imaging for the assessment of scoliosis deformities: application to postoperative 3D quantitative analysis of the trunk. Eur Spine J. 2014;23(Suppl 4):S397–405.PubMedGoogle Scholar
  51. 51.
    Caballero A, Barrios C, Burgos J, Hevia E, Correa C. Vertebral growth modulation by hemicircumferential electrocoagulation: an experimental study in pigs. Eur Spine J. 2011;20(Suppl 3):367–75.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Catanzariti JF, Agnani O, Guyot MA, Wlodyka-Demaille S, Khenioui H, Donze C. Does adolescent idiopathic scoliosis relate to vestibular disorders? A systematic review. Ann Phys Rehabil Med. 2014;57(6–7):465–79.PubMedCrossRefGoogle Scholar
  53. 53.
    Hawasli AH, Hullar TE, Dorward IG. Idiopathic scoliosis and the vestibular system. Eur Spine J. 2015;24(2):227–33.PubMedCrossRefGoogle Scholar
  54. 54.
    Hitier M, Hamon M, Denise P, Lacoudre J, Thenint MA, Mallet JF, et al. Lateral Semicircular Canal asymmetry in idiopathic scoliosis: an early link between biomechanical, hormonal and neurosensory theories? PLoS One. 2015;10(7):e0131120.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Noshchenko A, Hoffecker L, Lindley EM, Burger EL, Cain CM, Patel VV, et al. Predictors of spine deformity progression in adolescent idiopathic scoliosis: a systematic review with meta-analysis. World J Orthop. 2015;6(7):537–58.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Pialasse JP, Mercier P, Descarreaux M, Simoneau M. Sensorimotor control impairment in young adults with idiopathic scoliosis compared with healthy controls. J Manip Physiol Ther. 2016;39(7):473–9.CrossRefGoogle Scholar
  57. 57.
    Lambert FM, Malinvaud D, Glaunes J, Bergot C, Straka H, Vidal PP. Vestibular asymmetry as the cause of idiopathic scoliosis: a possible answer from Xenopus. J Neurosci. 2009;29(40):12477–83.PubMedCrossRefGoogle Scholar
  58. 58.
    Lambert FM, Malinvaud D, Gratacap M, Straka H, Vidal PP. Restricted neural plasticity in vestibulospinal pathways after unilateral labyrinthectomy as the origin for scoliotic deformations. J Neurosci. 2013;33(16):6845–56.PubMedCrossRefGoogle Scholar
  59. 59.
    Dahlhoff M, Emrich D, Wolf E, Schneider MR. Increased activation of the epidermal growth factor receptor in transgenic mice overexpressing epigen causes peripheral neuropathy. Biochim Biophys Acta. 2013;1832(12):2068–76.PubMedCrossRefGoogle Scholar
  60. 60.
    Smit JJ, Baas F, Hoogendijk JE, Jansen GH, van der Valk MA, Schinkel AH, et al. Peripheral neuropathy in mice transgenic for a human MDR3 P-glycoprotein mini-gene. J Neurosci. 1996;16(20):6386–93.PubMedCrossRefGoogle Scholar
  61. 61.
    Mogha A, Benesh AE, Patra C, Engel FB, Schoneberg T, Liebscher I, et al. Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation. J Neurosci. 2013;33(46):17976–85.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Karner CM, Long F, Solnica-Krezel L, Monk KR, Gray RS. Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice. Hum Mol Genet. 2015;24(15):4365–73.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Buchan JG, Gray RS, Gansner JM, Alvarado DM, Burgert L, Gitlin JD, et al. Kinesin family member 6 (kif6) is necessary for spine development in zebrafish. Dev Dyn. 2014;243(12):1646–57.PubMedCrossRefGoogle Scholar
  64. 64.
    Boswell CW, Ciruna B. Understanding idiopathic scoliosis: a new zebrafish School of Thought. Trends Genet. 2017;33(3):183–96.PubMedCrossRefGoogle Scholar
  65. 65.
    Yang Z, Xie Y, Chen J, Zhang D, Yang C, Li M. High selenium may be a risk factor of adolescent idiopathic scoliosis. Med Hypotheses. 2010;75(1):126–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Lloyd HMS, Kirchhoff CA. Case study: scoliosis in a bonobo (Pan paniscus). J Med Primatol. 2018 Apr;47(2):114–116. doi: 10.1111/jmp.12325. Epub 2017 Nov 29.CrossRefPubMedGoogle Scholar
  67. 67.
    Naique SB, Porter R, Cunningham AA, Hughes SP, Sanghera B, Amis AA. Scoliosis in an orangutan. Spine. 2003;28(7):E143–5.PubMedGoogle Scholar
  68. 68.
    Berghan J, VIsser IN. Vertebral column malformations in New Zealand delphinids with a review of cases world wide. Aquat Mamm. 2000;26(1):17–25.Google Scholar
  69. 69.
    Ambert AM, Samuelson MM, Pitchford JL, Solangi M. Visually detectable vertebral malformations of a bottlenose dolphin (Tursiops truncatus) in the Mississippi sound. Aquat Mamm. 2017;43(4):6.CrossRefGoogle Scholar
  70. 70.
    Andrews B, Davis W, Parham D. Corporate response and facilitation of the rehabilitation of a California gray whale calf. Acad Radiol. 2001;Aquatic Mammals 273:209–11.Google Scholar
  71. 71.
    Ellis Giddens W, Ryland M, Casson CJ. Idiopathic scoliosis in a Newborn Sea otter, Enhydra lutris (L.). J Wildl Dis. 1984;20(3):248–50.CrossRefGoogle Scholar
  72. 72.
    Mochida J, Benson DR, Abbott U, Rucker RB. Neuromorphometric changes in the ventral spinal roots in a scoliotic animal. Spine. 1993;18(3):350–5.PubMedCrossRefGoogle Scholar
  73. 73.
    Nakai S. Histological and histochemical changes in the neck muscles of spontaneously occurring scoliosis in a special strain of Japanese quail, SQOHM. Nihon Seikeigeka Gakkai Zasshi. 1990;64(4):229–39.PubMedGoogle Scholar
  74. 74.
    Sobajima S, Kin A, Baba I, Kanbara K, Semoto Y, Abe M. Implication for melatonin and its receptor in the spinal deformities of hereditary Lordoscoliotic rabbits. Spine. 2003;28(6):554–8.PubMedGoogle Scholar
  75. 75.
    Grimes DT, Boswell CW, Morante NF, Henkelman RM, Burdine RD, Ciruna B. Zebrafish models of idiopathic scoliosis link cerebrospinal fluid flow defects to spine curvature. Science. 2016;352(6291):1341–4.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Gorman KF, Tredwell SJ, Breden F. The mutant guppy syndrome curveback as a model for human heritable spinal curvature. Spine. 2007;32(7):735–41.PubMedCrossRefGoogle Scholar
  77. 77.
    Gorman KF, Christians JK, Parent J, Ahmadi R, Weigel D, Dreyer C, et al. A major QTL controls susceptibility to spinal curvature in the curveback guppy. BMC Genet. 2011;12(1):16.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Lieschke GJ, Currie PD. Animal models of human disease: zebrafish swim into view. Nat Rev Genet. 2007;8(5):353–67.PubMedCrossRefGoogle Scholar
  79. 79.
    Hwang WY, Fu Y, Reyon D, Maeder ML, Kaini P, Sander JD, et al. Heritable and precise zebrafish genome editing using a CRISPR-Cas system. PLoS One. 2013;8(7):e68708.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Auer TO, Duroure K, De Cian A, Concordet JP, Del Bene F. Highly efficient CRISPR/Cas9-mediated knock-in in zebrafish by homology-independent DNA repair. Genome Res. 2014;24(1):142–53.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Luderman LN, Unlu G, Knapik EW. Zebrafish developmental models of skeletal diseases. Curr Top Dev Biol. 2017;124:81–124.PubMedCrossRefGoogle Scholar
  82. 82.
    Fisher S, Jagadeeswaran P, Halpern ME. Radiographic analysis of zebrafish skeletal defects. Dev Biol. 2003;264(1):64–76.PubMedCrossRefGoogle Scholar
  83. 83.
    Henke K, Daane JM, Hawkins MB, Dooley CM, Busch-Nentwich EM, Stemple DL, et al. Genetic screen for postembryonic development in the zebrafish (Danio rerio): dominant mutations affecting adult form. Genetics. 2017;207(2):609–23.PubMedGoogle Scholar
  84. 84.
    Paul S, Schindler S, Giovannone D, de Millo Terrazzani A, Mariani FV, Crump JG. Ihha induces hybrid cartilage-bone cells during zebrafish jawbone regeneration. Development. 2016;143(12):2066–76.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Huitema LF, Apschner A, Logister I, Spoorendonk KM, Bussmann J, Hammond CL, et al. Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish. Proc Natl Acad Sci U S A. 2012;109(52):21372–7.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Mackay EW, Apschner A, Schulte-Merker S. Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI. Development. 2015;142(6):1095–101.PubMedCrossRefGoogle Scholar
  87. 87.
    Kou I, Takahashi Y, Johnson TA, Takahashi A, Guo L, Dai J, et al. Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nat Genet. 2013;45(6):676–9.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR, Dominguez C, et al. A G protein-coupled receptor is essential for Schwann cells to initiate myelination. Science. 2009;325(5946):1402–5.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Geng FS, Abbas L, Baxendale S, Holdsworth CJ, Swanson AG, Slanchev K, et al. Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene. Development. 2013;140(21):4362–74.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Takahashi Y, Kou I, Takahashi A, Johnson TA, Kono K, Kawakami N, et al. A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat Genet. 2011;43(12):1237–40.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Cao Y, Min J, Zhang Q, Li H, Li H. Associations of LBX1 gene and adolescent idiopathic scoliosis susceptibility: a meta-analysis based on 34,626 subjects. BMC Musculoskelet Disord. 2016;17:309.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Chettier R, Nelson L, Ogilvie JW, Albertsen HM, Ward K. Haplotypes at LBX1 have distinct inheritance patterns with opposite effects in adolescent idiopathic scoliosis. PLoS One. 2015;10(2):e0117708.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Londono D, Kou I, Johnson TA, Sharma S, Ogura Y, Tsunoda T, et al. A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups. J Med Genet. 2014;51(6):401–6.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Brohmann H, Jagla K, Birchmeier C. The role of Lbx1 in migration of muscle precursor cells. Development. 2000;127(2):437–45.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Kruger M, Schafer K, Braun T. The homeobox containing gene Lbx1 is required for correct dorsal-ventral patterning of the neural tube. J Neurochem. 2002;82(4):774–82.PubMedCrossRefGoogle Scholar
  96. 96.
    Muller T, Brohmann H, Pierani A, Heppenstall PA, Lewin GR, Jessell TM, et al. The homeodomain factor lbx1 distinguishes two major programs of neuronal differentiation in the dorsal spinal cord. Neuron. 2002;34(4):551–62.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Sieber MA, Storm R, Martinez-de-la-Torre M, Muller T, Wende H, Reuter K, et al. Lbx1 acts as a selector gene in the fate determination of somatosensory and viscerosensory relay neurons in the hindbrain. J Neurosci. 2007;27(18):4902–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Kilian B, Mansukoski H, Barbosa FC, Ulrich F, Tada M, Heisenberg CP. The role of Ppt/Wnt5 in regulating cell shape and movement during zebrafish gastrulation. Mech Dev. 2003;120(4):467–76.PubMedCrossRefGoogle Scholar
  99. 99.
    Madsen EC, Gitlin JD. Zebrafish mutants calamity and catastrophe define critical pathways of gene-nutrient interactions in developmental copper metabolism. PLoS Genet. 2008;4(11):e1000261.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Mendelsohn BA, Yin C, Johnson SL, Wilm TP, Solnica-Krezel L, Gitlin JD. Atp7a determines a hierarchy of copper metabolism essential for notochord development. Cell Metab. 2006;4(2):155–62.PubMedCrossRefGoogle Scholar
  101. 101.
    Hubaud A, Pourquie O. Signalling dynamics in vertebrate segmentation. Nat Rev Mol Cell Biol. 2014;15(11):709–21.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Yu X, Ng CP, Habacher H, Roy S. Foxj1 transcription factors are master regulators of the motile ciliogenic program. Nat Genet. 2008;40(12):1445–53.PubMedCrossRefGoogle Scholar
  103. 103.
    Parichy DM, Elizondo MR, Mills MG, Gordon TN, Engeszer RE. Normal table of postembryonic zebrafish development: staging by externally visible anatomy of the living fish. Dev Dyn. 2009;238(12):2975–3015.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Turgut M, Cullu E, Uysal A, Yurtseven ME, Alparslan B. Chronic changes in cerebrospinal fluid pathways produced by subarachnoid kaolin injection and experimental spinal cord trauma in the rabbit: their relationship with the development of spinal deformity. An electron microscopic study and magnetic resonance imaging evaluation. Neurosurg Rev. 2005;28(4):289–97.PubMedCrossRefGoogle Scholar
  105. 105.
    Chuma A, Kitahara H, Minami S, Goto S, Takaso M, Moriya H. Structural scoliosis model in dogs with experimentally induced syringomyelia. Spine. 1997;22(6):589–94. discussion 95PubMedCrossRefGoogle Scholar
  106. 106.
    Godzik J, Dardas A, Kelly MP, Holekamp TF, Lenke LG, Smyth MD, et al. Comparison of spinal deformity in children with Chiari I malformation with and without syringomyelia: matched cohort study. Eur Spine J. 2016;25(2):619–26.PubMedCrossRefGoogle Scholar
  107. 107.
    Ogura Y, Kou I, Takahashi Y, Takeda K, Minami S, Kawakami N, et al. A functional variant in MIR4300HG, the host gene of microRNA MIR4300 is associated with progression of adolescent idiopathic scoliosis. Hum Mol Genet. 2017;26(20):4086–92.PubMedCrossRefGoogle Scholar
  108. 108.
    Patten SA, Margaritte-Jeannin P, Bernard JC, Alix E, Labalme A, Besson A, et al. Functional variants of POC5 identified in patients with idiopathic scoliosis. J Clin Invest. 2015;125(3):1124–8.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Becker-Heck A, Zohn IE, Okabe N, Pollock A, Lenhart KB, Sullivan-Brown J, et al. The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nat Genet. 2011;43(1):79–84.PubMedCrossRefGoogle Scholar
  110. 110.
    Jaffe KM, Grimes DT, Schottenfeld-Roames J, Werner ME, Ku TS, Kim SK, et al. c21orf59/kurly controls both cilia motility and polarization. Cell Rep. 2016;14(8):1841–9.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Serluca FC, Xu B, Okabe N, Baker K, Lin SY, Sullivan-Brown J, et al. Mutations in zebrafish leucine-rich repeat-containing six-like affect cilia motility and result in pronephric cysts, but have variable effects on left-right patterning. Development. 2009;136(10):1621–31.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Sullivan-Brown J, Schottenfeld J, Okabe N, Hostetter CL, Serluca FC, Thiberge SY, et al. Zebrafish mutations affecting cilia motility share similar cystic phenotypes and suggest a mechanism of cyst formation that differs from pkd2 morphants. Dev Biol. 2008;314(2):261–75.PubMedCrossRefGoogle Scholar
  113. 113.
    Eisen JS, Smith JC. Controlling morpholino experiments: don’t stop making antisense. Development. 2008;135(10):1735–43.PubMedCrossRefGoogle Scholar
  114. 114.
    Kim HK, Aruwajoye O, Sucato D, Richards BS, Feng GS, Chen D, et al. Induction of SHP2 deficiency in chondrocytes causes severe scoliosis and kyphosis in mice. Spine. 2013;38(21):E1307–12.PubMedCrossRefGoogle Scholar
  115. 115.
    Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009;19(3):230–6.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Henry SP, Liang S, Akdemir KC, de Crombrugghe B. The postnatal role of Sox9 in cartilage. J Bone Miner Res. 2012;27(12):2511–25.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Akiyama H, Chaboissier MC, Martin JF, Schedl A, de Crombrugghe B. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 2002;16(21):2813–28.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Settle SH Jr, Rountree RB, Sinha A, Thacker A, Higgins K, Kingsley DM. Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. Dev Biol. 2003;254(1):116–30.PubMedCrossRefGoogle Scholar
  119. 119.
    Hartmann C, Tabin CJ. Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton. Cell. 2001;104(3):341–51.PubMedCrossRefGoogle Scholar
  120. 120.
    Lee WT, Cheung CS, Tse YK, Guo X, Qin L, Lam TP, et al. Association of osteopenia with curve severity in adolescent idiopathic scoliosis: a study of 919 girls. Osteoporos Int: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2005;16(12):1924–32.Google Scholar
  121. 121.
    Hung VW, Qin L, Cheung CS, Lam TP, Ng BK, Tse YK, et al. Osteopenia: a new prognostic factor of curve progression in adolescent idiopathic scoliosis. J Bone Joint Surg Am. 2005;87(12):2709–16.PubMedGoogle Scholar
  122. 122.
    Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet. 1996;12(4):390–7.PubMedCrossRefGoogle Scholar
  123. 123.
    Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell. 1996;84(6):911–21.PubMedCrossRefGoogle Scholar
  124. 124.
    Valverde-Franco G, Liu H, Davidson D, Chai S, Valderrama-Carvajal H, Goltzman D, et al. Defective bone mineralization and osteopenia in young adult FGFR3−/− mice. Hum Mol Genet. 2004;13(3):271–84.PubMedCrossRefGoogle Scholar
  125. 125.
    Valverde-Franco G, Binette JS, Li W, Wang H, Chai S, Laflamme F, et al. Defects in articular cartilage metabolism and early arthritis in fibroblast growth factor receptor 3 deficient mice. Hum Mol Genet. 2006;15(11):1783–92.PubMedCrossRefGoogle Scholar
  126. 126.
    Gao C, Chen BP, Sullivan MB, Hui J, Ouellet JA, Henderson JE, et al. Micro CT analysis of spine architecture in a mouse model of scoliosis. Front Endocrinol (Lausanne). 2015;6:38.Google Scholar
  127. 127.
    Clin J, Aubin CE, Parent S, Labelle H. A biomechanical study of the Charleston brace for the treatment of scoliosis. Spine. 2010;35(19):E940–7.PubMedCrossRefGoogle Scholar
  128. 128.
    MacIntyre NJ, Recknor CP, Grant SL, Recknor JC. Scores on the safe functional motion test predict incident vertebral compression fracture. Osteoporos Int : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2014;25(2):543–50.Google Scholar
  129. 129.
    Makrythanasis P, Temtamy S, Aglan MS, Otaify GA, Hamamy H, Antonarakis SE. A novel homozygous mutation in FGFR3 causes tall stature, severe lateral tibial deviation, scoliosis, hearing impairment, camptodactyly, and arachnodactyly. Hum Mutat. 2014;35(8):959–63.PubMedCrossRefGoogle Scholar
  130. 130.
    Komatsu Y, Chusho H, Tamura N, Yasoda A, Miyazawa T, Suda M, et al. Significance of C-type natriuretic peptide (CNP) in endochondral ossification: analysis of CNP knockout mice. J Bone Miner Metab. 2002;20(6):331–6.PubMedCrossRefGoogle Scholar
  131. 131.
    Tsuji T, Kunieda T. A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse. J Biol Chem. 2005;280(14):14288–92.PubMedCrossRefGoogle Scholar
  132. 132.
    Miura K, Kim OH, Lee HR, Namba N, Michigami T, Yoo WJ, et al. Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene. Am J Med Genet A. 2014;164A(1):156–63.PubMedCrossRefGoogle Scholar
  133. 133.
    Miura K, Namba N, Fujiwara M, Ohata Y, Ishida H, Kitaoka T, et al. An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene. PLoS One. 2012;7(8):e42180.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Waller-Evans H, Promel S, Langenhan T, Dixon J, Zahn D, Colledge WH, et al. The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse. PLoS One. 2010;5(11):e14047.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Monk KR, Oshima K, Jors S, Heller S, Talbot WS. Gpr126 is essential for peripheral nerve development and myelination in mammals. Development. 2011;138(13):2673–80.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Brochhausen C, Turial S, Muller FK, Schmitt VH, Coerdt W, Wihlm JM, et al. Pectus excavatum: history, hypotheses and treatment options. Interact Cardiovasc Thorac Surg. 2012;14(6):801–6.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Wu S, Sun X, Zhu W, Huang Y, Mou L, Liu M, et al. Evidence for GAL3ST4 mutation as the potential cause of pectus excavatum. Cell Res. 2012;22(12):1712–5.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Lefebvre V, Bhattaram P. Vertebrate skeletogenesis. Curr Top Dev Biol. 2010;90:291–317.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Fleming A, Keynes R, Tannahill D. A central role for the notochord in vertebral patterning. Development. 2004;131(4):873–80.PubMedCrossRefGoogle Scholar
  140. 140.
    Grotmol S, Kryvi H, Nordvik K, Totland GK. Notochord segmentation may lay down the pathway for the development of the vertebral bodies in the Atlantic salmon. Anat Embryol (Berl). 2003;207(4–5):263–72.CrossRefGoogle Scholar
  141. 141.
    Haga Y, Dominique VJ 3rd, Du SJ. Analyzing notochord segmentation and intervertebral disc formation using the twhh: gfp transgenic zebrafish model. Transgenic Res. 2009;18(5):669–83.PubMedCrossRefGoogle Scholar
  142. 142.
    Cortes DH, Elliott DM. The intervertebral disc: overview of disc mechanics. In: Shapiro IM, Risbud MV, editors. The intervertebral disc: molecular and structural studies of the disc in health and disease. Vienna: Springer; 2014. p. 17–31.CrossRefGoogle Scholar
  143. 143.
    Bruggeman BJ, Maier JA, Mohiuddin YS, Powers R, Lo Y, Guimaraes-Camboa N, et al. Avian intervertebral disc arises from rostral sclerotome and lacks a nucleus pulposus: implications for evolution of the vertebrate disc. Dev Dyn. 2012;241(4):675–83.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Inohaya K, Takano Y, Kudo A. The teleost intervertebral region acts as a growth center of the centrum: in vivo visualization of osteoblasts and their progenitors in transgenic fish. Dev Dyn. 2007;236(11):3031–46.PubMedCrossRefGoogle Scholar
  145. 145.
    Irie K, Kuroda Y, Mimori N, Hayashi S, Abe M, Tsuji N, et al. Histopathology of a wavy medaka. J Toxicol Pathol. 2016;29(2):115–8.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Pereira L, Lee SY, Gayraud B, Andrikopoulos K, Shapiro SD, Bunton T, et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci U S A. 1999;96(7):3819–23.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Dickinson ME, Flenniken AM, Ji X, Teboul L, Wong MD, White JK, et al. High-throughput discovery of novel developmental phenotypes. Nature. 2016;537(7621):508–14.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Meehan TF, Conte N, West DB, Jacobsen JO, Mason J, Warren J, et al. Disease model discovery from 3,328 gene knockouts by the international mouse phenotyping consortium. Nat Genet. 2017;49(8):1231–8.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PediatricsThe University of Texas at Austin Dell Medical SchoolAustinUSA

Personalised recommendations