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Animal Models for Understanding Human Skeletal Defects

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Animal Models of Human Birth Defects

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1236))

Abstract

Skeletal defects, such as cleft palate, scoliosis, and shortening of the limb bones are common in the human population. Animal models have been essential for characterizing the molecular and cellular mechanisms that underlie these and other skeletal disorders. This chapter will explore the cellular origins of the vertebrate skeleton and introduce a selection of animal models for human disorders of the skull and facial bones, spinal column, and limbs. The common genetic pathways that build the skeleton of various vertebrate species and how these similarities facilitate the study of human developmental processes in laboratory animals will be a focus of discussion. This chapter will also highlight how current genome editing technologies can be applied to model various perturbations of human chromatin structure in laboratory animals.

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References

  1. Calder AD, Foley P. Skeletal dysplasias: an overview. Paediatr Child Health (Oxford). 2018;28(2):84–92.

    Article  Google Scholar 

  2. Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet Part A. 2015;167(12):2869–92.

    Article  CAS  Google Scholar 

  3. Eicher EM, Southard JL, Scriver CR, Glorieux FH. Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets. Proc Natl Acad Sci U S A. 1976;73(12):4667–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Selby PB, Selby PR. Gamma-ray-induced dominant mutations that cause skeletal abnormalities in mice I. Plan, summary of results and discussion. Mutat Res Mol Mech Mutagen. 1977;43(3):357–75.

    Article  CAS  Google Scholar 

  5. Sillence DO, Ritchie HE, Selby PB, Prieur DJ. Animal model: skeletal anomalies in mice with cleidocranial dysplasia. Am J Med Genet. 1987;27(1):75–85.

    Article  CAS  PubMed  Google Scholar 

  6. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell. 1997;89(5):765–71.

    Article  CAS  PubMed  Google Scholar 

  7. Mundlos S, Otto F, Mundlos C, Mulliken J, Aylsworth A, Albright S, et al. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell. 1997;89(5):773–9.

    Article  CAS  PubMed  Google Scholar 

  8. Haffter P, Granato M, Brand M, Mullins MC, Hammerschmidt M, Kane DA, et al. The identification of genes with unique and essential functions in the development of the zebrafish, Danio rerio. Development. 1996;123(1).

    Google Scholar 

  9. Driever W, Solnica-Krezel L, Schier AF, Neuhauss SC, Malicki J, Stemple DL, et al. A genetic screen for mutations affecting embryogenesis in zebrafish. Development. 1996;123:37–46.

    CAS  PubMed  Google Scholar 

  10. Schilling TF, Piotrowski T, Grandel H, Brand M, Heisenberg CP, Jiang YJ, et al. Jaw and branchial arch mutants in zebrafish I: branchial arches. Development. 1996;123:329–44.

    CAS  PubMed  Google Scholar 

  11. Piotrowski T, Schilling TF, Brand M, Jiang YJ, Heisenberg CP, Beuchle D, et al. Jaw and branchial arch mutants in zebrafish II: anterior arches and cartilage differentiation. Development. 1996;123:345–56.

    CAS  PubMed  Google Scholar 

  12. van Eeden FJ, Granato M, Schach U, Brand M, Furutani-Seiki M, Haffter P, et al. Genetic analysis of fin formation in the zebrafish, Danio rerio. Development. 1996;123:255–62.

    PubMed  Google Scholar 

  13. van Eeden FJ, Granato M, Schach U, Brand M, Furutani-Seiki M, Haffter P, et al. Mutations affecting somite formation and patterning in the zebrafish, Danio rerio. Development. 1996;123(1):153–64.

    PubMed  Google Scholar 

  14. Neuhauss SC, Solnica-Krezel L, Schier AF, Zwartkruis F, Stemple DL, Malicki J, et al. Mutations affecting craniofacial development in zebrafish. Development. 1996;123:357–67.

    CAS  PubMed  Google Scholar 

  15. Howe DG, Bradford YM, Conlin T, Eagle AE, Fashena D, Frazer K, Knight J, Mani P, Martin R, Moxon SA, Paddock H, Pich C, Ramachandran S, Ruef BJ, Ruzicka L, Schaper K, Shao X, Singer A, Sprunger B, Van Slyke CE, Westerfield M. ZFIN, the Zebrafish Model Organism Database: increased support for mutants and transgenics. Nucleic Acids Res. 2013;41(Database issue):D854–60.

    CAS  PubMed  Google Scholar 

  16. Muenke M. Finding genes involved in human developmental disorders. Curr Opin Genet Dev. 1995;5(3):354–61.

    Article  CAS  PubMed  Google Scholar 

  17. Shiang R, Thompson LM, Zhu Y-Z, Church DM, Fielder TJ, Bocian M, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell. 1994;78(2):335–42.

    Article  CAS  PubMed  Google Scholar 

  18. Tavormina PL, Shiang R, Thompson LM, Zhu Y-Z, Wilkin DJ, Lachman RS, et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet. 1995;9(3):321–8.

    Article  CAS  PubMed  Google Scholar 

  19. Wilkie AOM, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995;9(2):165–72.

    Article  CAS  PubMed  Google Scholar 

  20. Reardon W, Winter RM, Rutland P, Pulleyn LJ, Jones BM, Malcolm S. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet. 1994;8(1):98–103.

    Article  CAS  PubMed  Google Scholar 

  21. Schell U, Hehr A, Feldman GJ, Robin NH, Zackai EH, de Die-Smulders C, et al. Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. Hum Mol Genet. 1995;4(3):323–8.

    Article  CAS  PubMed  Google Scholar 

  22. Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell. 1994;79(6):1111–20.

    Article  CAS  PubMed  Google Scholar 

  23. Thomas KR, Capecchi MR. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell. 1987;51(3):503–12.

    Article  CAS  PubMed  Google Scholar 

  24. Mansour SL, Thomas KR, Capecchi MR. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature. 1988;336(6197):348–52.

    Article  CAS  PubMed  Google Scholar 

  25. Doetschman T, Maeda N, Smithies O. Targeted mutation of the Hprt gene in mouse embryonic stem cells. Proc Natl Acad Sci U S A. 1988;85(22):8583–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Thompson S, Clarke AR, Pow AM, Hooper ML, Melton DW. Germ line transmission and expression of a corrected HPRT gene produced by gene targeting in embryonic stem cells. Cell. 1989;56(2):313–21.

    Article  CAS  PubMed  Google Scholar 

  27. Koller BH, Hagemann LJ, Doetschman T, Hagaman JR, Huang S, Williams PJ, et al. Germ-line transmission of a planned alteration made in a hypoxanthine phosphoribosyltransferase gene by homologous recombination in embryonic stem cells. Proc Natl Acad Sci U S A. 1989;86(22):8927–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Schwartzberg PL, Goff SP, Robertson EJ. Germ-line transmission of a c-abl mutation produced by targeted gene disruption in ES cells. Science. 1989;246(4931):799–803.

    Article  CAS  PubMed  Google Scholar 

  29. Koller BH, Marrack P, Kappler JW, Smithies O. Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells. Science. 1990;248(4960):1227–30.

    Article  CAS  PubMed  Google Scholar 

  30. Chisaka O, Capecchi MR. Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5. Nature. 1991;350(6318):473–9.

    Article  CAS  PubMed  Google Scholar 

  31. Davis AP, Witte DP, Hsieh-Li HM, Potter SS, Capecchi MR. Absence of radius and ulna in mice lacking hoxa-11 and hoxd-11. Nature. 1995;375(6534):791–5.

    Article  CAS  PubMed  Google Scholar 

  32. Kostic D, Capecchi MR. Targeted disruptions of the murine Hoxa-4 and Hoxa-6 genes result in homeotic transformations of components of the vertebral column. Mech Dev. 1994;46(3):231–47.

    Article  CAS  PubMed  Google Scholar 

  33. Fromental-Ramain C, Warot X, Lakkaraju S, Favier B, Haack H, Birling C, et al. Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning. Development. 1996;122(2):461–72.

    CAS  PubMed  Google Scholar 

  34. Zakany J, Duboule D. The role of Hox genes during vertebrate limb development. Curr Opin Genet Dev. 2007;17(4):359–66.

    Article  CAS  PubMed  Google Scholar 

  35. Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B. Sox9 is required for cartilage formation. Nat Genet. 1999;22(1):85–9.

    Article  CAS  PubMed  Google Scholar 

  36. Chen ZF, Behringer RR. twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 1995;9(6):686–99.

    Article  CAS  PubMed  Google Scholar 

  37. Bourgeois P, Bolcato-Bellemin AL, Danse JM, Bloch-Zupan A, Yoshiba K, Stoetzel C, et al. The variable expressivity and incomplete penetrance of the twist-null heterozygous mouse phenotype resemble those of human Saethre-Chotzen syndrome. Hum Mol Genet. 1998;7(6):945–57.

    Article  CAS  PubMed  Google Scholar 

  38. Carver EA, Oram KF, Gridley T. Craniosynostosis in Twist heterozygous mice: a model for Saethre-Chotzen syndrome. Anat Rec. 2002;268(2):90–2.

    Article  PubMed  Google Scholar 

  39. Saga Y, Hata N, Koseki H, Taketo MM. Mesp2: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation. Genes Dev. 1997;11(14):1827–39.

    Article  CAS  PubMed  Google Scholar 

  40. Evrard YA, Lun Y, Aulehla A, Gan L, Johnson RL. lunatic fringe is an essential mediator of somite segmentation and patterning. Nature. 1998;394(6691):377–81.

    Article  CAS  PubMed  Google Scholar 

  41. Whittock NV, Sparrow DB, Wouters MA, Sillence D, Ellard S, Dunwoodie SL, et al. Mutated MESP2 causes spondylocostal dysostosis in humans. Am J Hum Genet. 2004;74(6):1249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sparrow DB, Chapman G, Wouters MA, Whittock NV, Ellard S, Fatkin D, et al. Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am J Hum Genet. 2006;78(1):28–37.

    Article  CAS  PubMed  Google Scholar 

  43. Ayadi A, Birling M-C, Bottomley J, Bussell J, Fuchs H, Fray M, et al. Mouse large-scale phenotyping initiatives: overview of the European Mouse Disease Clinic (EUMODIC) and of the Wellcome Trust Sanger Institute Mouse Genetics Project. Mamm Genome. 2012;23(9–10):600–10.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kabir M, Barradas A, Tzotzos GT, Hentges KE, Doig AJ. Properties of genes essential for mouse development. PLoS One. 2017;12(5):e0178273. Zou Q, editor.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Jiao K, Kulessa H, Tompkins K, Zhou Y, Batts L, Baldwin HS, et al. An essential role of Bmp4 in the atrioventricular septation of the mouse heart. Genes Dev. 2003;17(19):2362–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fujiwara T, Dunn NR, Hogan BLM. Bone morphogenetic protein 4 in the extraembryonic mesoderm is required for allantois development and the localization and survival of primordial germ cells in the mouse. Proc Natl Acad Sci U S A. 2001;98(24):13739–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Winnier G, Blessing M, Labosky PA, Hogan BL. Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev. 1995;9(17):2105–16.

    Article  CAS  PubMed  Google Scholar 

  48. Selever J, Liu W, Lu M-F, Behringer RR, Martin JF. Bmp4 in limb bud mesoderm regulates digit pattern by controlling AER development. Dev Biol. 2004;276(2):268–79.

    Article  CAS  PubMed  Google Scholar 

  49. Liu W, Selever J, Murali D, Sun X, Brugger SM, Ma L, et al. Threshold-specific requirements for Bmp4 in mandibular development. Dev Biol. 2005;283(2):282–93.

    Article  CAS  PubMed  Google Scholar 

  50. St-Jacques B, Hammerschmidt M, McMahon AP. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 1999;13(16):2072–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Maeda Y, Nakamura E, Nguyen M-T, Suva LJ, Swain FL, Razzaque MS, et al. Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone. Proc Natl Acad Sci U S A. 2007;104(15):6382–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Feil R, Brocard J, Mascrez B, LeMeur M, Metzger D, Chambon P. Ligand-activated site-specific recombination in mice. Proc Natl Acad Sci U S A. 1996;93(20):10887–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Elefteriou F, Yang X. Genetic mouse models for bone studies—strengths and limitations. Bone. 2011;49(6):1242–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Doyon Y, McCammon JM, Miller JC, Faraji F, Ngo C, Katibah GE, et al. Heritable targeted gene disruption in zebrafish using designed zinc-finger nucleases. Nat Biotechnol. 2008;26(6):702–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Meng X, Noyes MB, Zhu LJ, Lawson ND, Wolfe SA. Targeted gene inactivation in zebrafish using engineered zinc-finger nucleases. Nat Biotechnol. 2008;26(6):695–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Huang P, Xiao A, Zhou M, Zhu Z, Lin S, Zhang B. Heritable gene targeting in zebrafish using customized TALENs. Nat Biotechnol. 2011;29(8):699–700.

    Article  PubMed  CAS  Google Scholar 

  58. Takeuchi JK, Koshiba-Takeuchi K, Suzuki T, Kamimura M, Ogura K, Ogura T. Tbx5 and Tbx4 trigger limb initiation through activation of the Wnt/Fgf signaling cascade. Development. 2003;130(12):2729–39.

    Article  CAS  PubMed  Google Scholar 

  59. Rallis C, Bruneau BG, Del Buono J, Seidman CE, Seidman JG, Nissim S, et al. Tbx5 is required for forelimb bud formation and continued outgrowth. Development. 2003;130(12):2741–51.

    Article  CAS  PubMed  Google Scholar 

  60. Roy B, Zhao J, Yang C, Luo W, Xiong T, Li Y, et al. CRISPR/Cascade 9-mediated genome editing-challenges and opportunities. Front Genet. 2018;9:240.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Kraft K, Geuer S, Will AJ, Chan WL, Paliou C, Borschiwer M, et al. Deletions, inversions, duplications: engineering of structural variants using CRISPR/Cas in mice. Cell Rep. 2015;10(5):833–9.

    Article  CAS  PubMed  Google Scholar 

  62. Spielmann M, Kakar N, Tayebi N, Leettola C, Nürnberg G, Sowada N, et al. Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice. Genome Res. 2016;26(2):183–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lupianez DG, Kraft K, Heinrich V, Krawitz P, Brancati F, Klopocki E, et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell. 2015;161(5):1012–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. D’Souza RN, Ruest L-B, Hinton RJ, Svoboda KKH. Development of the craniofacial complex. In: Bone and development. London: Springer; 2010. p. 153–81.

    Chapter  Google Scholar 

  65. Hubaud A, Pourquié O. Signalling dynamics in vertebrate segmentation. Nat Rev Mol Cell Biol. 2014;15(11):709–21.

    Article  CAS  PubMed  Google Scholar 

  66. Scaal M. Early development of the vertebral column. Semin Cell Dev Biol. 2016;49:83–91.

    Article  PubMed  Google Scholar 

  67. Kozhemyakina E, Lassar AB, Zelzer E. A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development. 2015;142(5):817–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cole RK. The “talpid lethal” in the domestic fowl. J Hered. 1942;33(3):83–6.

    Article  Google Scholar 

  69. Abbott UK, Taylor LW, Abplanalp H. A second talpid-like mutation in the fowl. Poult Sci. 1959;38:1185.

    Article  Google Scholar 

  70. Ede DA, Kelly WA. Developmental abnormalities in the head region of the Talpid mutant of the fowl. J Embryol Exp Morphol. 1964;12:161–82.

    CAS  PubMed  Google Scholar 

  71. Ede DA, Kelly WA. Developmental abnormalities in the trunk and limbs of the Talpid3 mutant of the fowl. J Embryol Exp Morphol. 1964;12:339–56.

    CAS  PubMed  Google Scholar 

  72. Chang C-F, Schock EN, O’Hare EA, Dodgson J, Cheng HH, Muir WM, et al. The cellular and molecular etiology of the craniofacial defects in the avian ciliopathic mutant talpid2. Development. 2014;141(15):3003–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Davey MG, Paton IR, Yin Y, Schmidt M, Bangs FK, Morrice DR, et al. The chicken talpid3 gene encodes a novel protein essential for Hedgehog signaling. Genes Dev. 2006;20(10):1365–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Knight RD, Nair S, Nelson SS, Afshar A, Javidan Y, Geisler R, et al. lockjaw encodes a zebrafish tfap2a required for early neural crest development. Development. 2003;130(23):5755–68.

    Article  CAS  PubMed  Google Scholar 

  75. Barrallo-Gimeno A, Holzschuh J, Driever W, Knapik EW. Neural crest survival and differentiation in zebrafish depends on mont blanc/tfap2a gene function. Development. 2004;131(7):1463–77.

    Article  CAS  PubMed  Google Scholar 

  76. Luo T, Lee Y-H, Saint-Jeannet J-P, Sargent TD. Induction of neural crest in Xenopus by transcription factor AP2alpha. Proc Natl Acad Sci U S A. 2003;100(2):532–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Brewer S, Feng W, Huang J, Sullivan S, Williams T. Wnt1-Cre-mediated deletion of AP-2alpha causes multiple neural crest-related defects. Dev Biol. 2004;267(1):135–52.

    Article  CAS  PubMed  Google Scholar 

  78. Milunsky JM, Maher TA, Zhao G, Roberts AE, Stalker HJ, Zori RT, et al. TFAP2A mutations result in branchio-oculo-facial syndrome. Am J Hum Genet. 2008;82(5):1171–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Franco B, Thauvin-Robinet C. Update on oral-facial-digital syndromes (OFDS). Cilia. 2016;5:12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Bruel A-L, Franco B, Duffourd Y, Thevenon J, Jego L, Lopez E, et al. Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes. J Med Genet. 2017;54(6):371–80.

    Article  CAS  PubMed  Google Scholar 

  81. Gurrieri F, Franco B, Toriello H, Neri G. Oral–facial–digital syndromes: review and diagnostic guidelines. Am J Med Genet Part A. 2007;143A(24):3314–23.

    Article  PubMed  Google Scholar 

  82. Thauvin-Robinet C, Cossée M, Cormier-Daire V, Van Maldergem L, Toutain A, Alembik Y, et al. Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: a French and Belgian collaborative study. J Med Genet. 2005;43(1):54–61.

    Article  CAS  Google Scholar 

  83. Schock EN, Chang C-F, Youngworth IA, Davey MG, Delany ME, Brugmann SA. Utilizing the chicken as an animal model for human craniofacial ciliopathies. Dev Biol. 2016;415(2):326–37.

    Article  CAS  PubMed  Google Scholar 

  84. Ferrante MI, Giorgio G, Feather SA, Bulfone A, Wright V, Ghiani M, et al. Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet. 2001;68(3):569–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Romio L, Fry AM, Winyard PJD, Malcolm S, Woolf AS, Feather SA. OFD1 is a centrosomal/basal body protein expressed during mesenchymal-epithelial transition in human nephrogenesis. J Am Soc Nephrol. 2004;15(10):2556–68.

    Article  CAS  PubMed  Google Scholar 

  86. Thauvin-Robinet C, Lee JS, Lopez E, Herranz-Pérez V, Shida T, Franco B, et al. The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation. Nat Genet. 2014;46(8):905–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hoover AN, Wynkoop A, Zeng H, Jia J, Niswander LA, Liu A. C2cd3 is required for cilia formation and Hedgehog signaling in mouse. Development. 2008;135(24):4049–58.

    Article  CAS  PubMed  Google Scholar 

  88. Ye X, Zeng H, Ning G, Reiter JF, Liu A. C2cd3 is critical for centriolar distal appendage assembly and ciliary vesicle docking in mammals. Proc Natl Acad Sci U S A. 2014;111(6):2164–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cortés CR, McInerney-Leo AM, Vogel I, Rondón Galeano MC, Leo PJ, Harris JE, et al. Mutations in human C2CD3 cause skeletal dysplasia and provide new insights into phenotypic and cellular consequences of altered C2CD3 function. Sci Rep. 2016;6:24083.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Lerner IM. Genetic homeostasis. New York: Wiley; 1954.

    Google Scholar 

  91. Lerner IM. The genetic basis of selection. New York: Wiley; 1958.

    Google Scholar 

  92. Abbott UK, Taylor LW, Abplanalp H. Studies with Talpid2, an embryonic lethal of the fowl. J Hered. 1960;51(5):195–202.

    Article  Google Scholar 

  93. Brugmann SA, Allen NC, James AW, Mekonnen Z, Madan E, Helms JA. A primary cilia-dependent etiology for midline facial disorders. Hum Mol Genet. 2010;19(8):1577–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Schock EN, Chang C-F, Struve JN, Chang Y-T, Chang J, Delany ME, et al. Using the avian mutant talpid2 as a disease model for understanding the oral-facial phenotypes of oral-facial-digital syndrome. Dis Model Mech. 2015;8(8):855–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Schneider RA, Hu D, Helms JA. From head to toe: conservation of molecular signals regulating limb and craniofacial morphogenesis. Cell Tissue Res. 1999;296(1):103–9.

    Article  CAS  PubMed  Google Scholar 

  96. Caruccio NC, Martinez-Lopez A, Harris M, Dvorak L, Bitgood J, Simandl BK, et al. Constitutive activation of sonic Hedgehog signaling in the chicken mutant talpid2: Shh-independent outgrowth and polarizing activity. Dev Biol. 1999;212(1):137–49.

    Article  CAS  PubMed  Google Scholar 

  97. Pak E, Segal RA. Hedgehog signal transduction: key players, oncogenic drivers, and cancer therapy. Dev Cell. 2016;38(4):333–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chang Y-T, Chaturvedi P, Schock EN, Brugmann SA. Understanding mechanisms of GLI-mediated transcription during craniofacial development and disease using the ciliopathic mutant, talpid2. Front Physiol. 2016;7:468.

    PubMed  PubMed Central  Google Scholar 

  99. Stephen LA, Tawamie H, Davis GM, Tebbe L, Nürnberg P, Nürnberg G, et al. TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23). Elife. 2015;4:e08077.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Parisi MA. Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet Part C Semin Med Genet. 2009;151C(4):326–40.

    Article  CAS  PubMed  Google Scholar 

  101. Bachmann-Gagescu R, Phelps IG, Dempsey JC, Sharma VA, Ishak GE, Boyle EA, et al. KIAA0586 is mutated in Joubert syndrome. Hum Mutat. 2015;36(9):831–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lewis KE, Drossopoulou G, Paton IR, Morrice DR, Robertson KE, Burt DW, et al. Expression of ptc and gli genes in talpid3 suggests bifurcation in Shh pathway. Development. 1999;126(11):2397–407.

    CAS  PubMed  Google Scholar 

  103. Buxton P, Francis-West PH, Davey MG, Tickle C, Paton IR, Morrice DR, et al. Craniofacial development in the talpid3 chicken mutant. Differentiation. 2004;72(7):348–62.

    Article  CAS  PubMed  Google Scholar 

  104. Li J, Wang C, Wu C, Cao T, Xu G, Meng Q, et al. PKA-mediated Gli2 and Gli3 phosphorylation is inhibited by Hedgehog signaling in cilia and reduced in Talpid3 mutant. Dev Biol. 2017;429(1):147–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yin Y, Bangs F, Paton IR, Prescott A, James J, Davey MG, et al. The Talpid3 gene (KIAA0586) encodes a centrosomal protein that is essential for primary cilia formation. Development. 2009;136(4):655–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kobayashi T, Kim S, Lin Y-C, Inoue T, Dynlacht BD. The CP110-interacting proteins Talpid3 and Cep290 play overlapping and distinct roles in cilia assembly. J Cell Biol. 2014;204(2):215–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wang L, Failler M, Fu W, Dynlacht BD. A distal centriolar protein network controls organelle maturation and asymmetry. Nat Commun. 2018;9(1):3938.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Lin AE, Gorlin RJ, Lurie IW, Brunner HG, van der Burgt I, Naumchik IV, et al. Further delineation of the branchio-oculo-facial syndrome. Am J Med Genet. 1995;56(1):42–59.

    Article  CAS  PubMed  Google Scholar 

  109. Stoetzel C, Riehm S, Bennouna Greene V, Pelletier V, Vigneron J, Leheup B, et al. Confirmation of TFAP2A gene involvement in branchio-oculo-facial syndrome (BOFS) and report of temporal bone anomalies. Am J Med Genet Part A. 2009;149A(10):2141–6.

    Article  CAS  PubMed  Google Scholar 

  110. Carter MT, Blaser S, Papsin B, Meschino W, Reardon W, Klatt R, et al. Middle and inner ear malformations in mutation-proven branchio-oculo-facial (BOF) syndrome: case series and review of the literature. Am J Med Genet Part A. 2012;158A(8):1977–81.

    Article  PubMed  Google Scholar 

  111. Li H, Sheridan R, Williams T. Analysis of TFAP2A mutations in branchio-oculo-facial syndrome indicates functional complexity within the AP-2α DNA-binding domain. Hum Mol Genet. 2013;22(16):3195–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Simoes-Costa M, Bronner ME. Establishing neural crest identity: a gene regulatory recipe. Development. 2015;142(2):242–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Swartz ME, Sheehan-Rooney K, Dixon MJ, Eberhart JK. Examination of a palatogenic gene program in zebrafish. Dev Dyn. 2011;240(9):2204–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mork L, Crump G. Zebrafish craniofacial development: a window into early patterning. Curr Top Dev Biol. 2015;115:235–69.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Frisdal A, Trainor PA. Development and evolution of the pharyngeal apparatus. Wiley Interdiscip Rev Dev Biol. 2014;3(6):403–18.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Wang W-D, Melville DB, Montero-Balaguer M, Hatzopoulos AK, Knapik EW. Tfap2a and Foxd3 regulate early steps in the development of the neural crest progenitor population. Dev Biol. 2011;360(1):173–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. de Crozé N, Maczkowiak F, Monsoro-Burq AH. Reiterative AP2a activity controls sequential steps in the neural crest gene regulatory network. Proc Natl Acad Sci U S A. 2011;108(1):155–60.

    Article  PubMed  Google Scholar 

  118. Schorle H, Meier P, Buchert M, Jaenisch R, Mitchell PJ. Transcription factor AP-2 essential for cranial closure and craniofacial development. Nature. 1996;381(6579):235–8.

    Article  CAS  PubMed  Google Scholar 

  119. Zhang J, Hagopian-Donaldson S, Serbedzija G, Elsemore J, Plehn-Dujowich D, McMahon AP, et al. Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. Nature. 1996;381(6579):238–41.

    Article  CAS  PubMed  Google Scholar 

  120. Green RM, Feng W, Phang T, Fish JL, Li H, Spritz RA, et al. Tfap2a-dependent changes in mouse facial morphology result in clefting that can be ameliorated by a reduction in Fgf8 gene dosage. Dis Model Mech. 2015;8(1):31–43.

    Article  CAS  PubMed  Google Scholar 

  121. Dunwoodie SL, Clements M, Sparrow DB, Sa X, Conlon RA, Beddington RSP. Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development. 2002;129(7):1795–806.

    CAS  PubMed  Google Scholar 

  122. Penton AL, Leonard LD, Spinner NB. Notch signaling in human development and disease. Semin Cell Dev Biol. 2012;23(4):450–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Giampietro PF, Dunwoodie SL, Kusumi K, Pourquié 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(1):38–67.

    Article  CAS  PubMed  Google Scholar 

  124. Hoppenfeld S, Lonner B, Murthy V, Gu Y. The rib epiphysis and other growth centers as indicators of the end of spinal growth. Spine (Phila Pa 1976). 2004;29(1):47–50.

    Article  Google Scholar 

  125. Wang S, Qiu Y, Zhu Z, Ma Z, Xia C, Zhu F. Histomorphological study of the spinal growth plates from the convex side and the concave side in adolescent idiopathic scoliosis. J Orthop Surg Res. 2007;2(1):19.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Day G, Frawley K, Phillips G, McPhee IB, Labrom R, Askin G, et al. The vertebral body growth plate in scoliosis: a primary disturbance of growth? Scoliosis. 2008;3(1):3.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Konieczny MR, Senyurt H, Krauspe R. Epidemiology of adolescent idiopathic scoliosis. J Child Orthop. 2013;7(1):3–9.

    Article  PubMed  Google Scholar 

  128. Jada A, Mackel CE, Hwang SW, Samdani AF, Stephen JH, Bennett JT, et al. Evaluation and management of adolescent idiopathic scoliosis: a review. Neurosurg Focus. 2017;43(4):E2.

    Article  PubMed  Google Scholar 

  129. Boswell CW, Ciruna B. Understanding idiopathic scoliosis: a new zebrafish school of thought. Trends Genet. 2017;33(3):183–96.

    Article  CAS  PubMed  Google Scholar 

  130. 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(1):4777.

    Article  CAS  PubMed  Google Scholar 

  131. Yang N, Wu N, Zhang L, Zhao Y, Liu J, Liang X, et al. TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice. Hum Mol Genet. 2019;28(4):539–47.

    Article  CAS  PubMed  Google Scholar 

  132. Gorman KF, Breden F. Idiopathic-type scoliosis is not exclusive to bipedalism. Med Hypotheses. 2009;72(3):348–52.

    Article  CAS  PubMed  Google Scholar 

  133. Gorman KF, Tredwell SJ, Breden F. The mutant guppy syndrome curveback as a model for human heritable spinal curvature. Spine (Phila Pa 1976). 2007;32(7):735–41.

    Article  Google Scholar 

  134. Hayes M, Naito M, Daulat A, Angers S, Ciruna B. Ptk7 promotes non-canonical Wnt/PCP-mediated morphogenesis and inhibits Wnt/β-catenin-dependent cell fate decisions during vertebrate development. Development. 2013;140(8):1807–18.

    Article  CAS  PubMed  Google Scholar 

  135. Lu X, Borchers AGM, Jolicoeur C, Rayburn H, Baker JC, Tessier-Lavigne M. PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature. 2004;430(6995):93–8.

    Article  CAS  PubMed  Google Scholar 

  136. Shnitsar I, Borchers A. PTK7 recruits dsh to regulate neural crest migration. Development. 2008;135(24):4015–24.

    Article  CAS  PubMed  Google Scholar 

  137. Bin-Nun N, Lichtig H, Malyarova A, Levy M, Elias S, Frank D. PTK7 modulates Wnt signaling activity via LRP6. Development. 2014;141(2):410–21.

    Article  CAS  PubMed  Google Scholar 

  138. Berger H, Wodarz A, Borchers A. PTK7 faces the Wnt in development and disease. Front Cell Dev Biol. 2017;5:31.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Wang M, De Marco P, Merello E, Drapeau P, Capra V, Kibar Z. Role of the planar cell polarity gene Protein tyrosine kinase 7 in neural tube defects in humans. Birth Defects Res Part A Clin Mol Teratol. 2015;103(12):1021–7.

    Article  CAS  Google Scholar 

  140. Lei Y, Kim S, Chen Z, Cao X, Zhu H, Yang W, et al. Variants identified in PTK7 associated with neural tube defects. Mol Genet Genomic Med. 2019;7(4):e00584.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Grimes DT, Boswell CW, Morante NFC, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Verhoef M, Barf H, Post M, van Asbeck F, Gooskens R, Prevo A. Secondary impairments in young adults with spina bifida. Dev Med Child Neurol. 2004;46(06):420–7.

    Article  CAS  PubMed  Google Scholar 

  143. Brinker T, Stopa E, Morrison J, Klinge P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS. 2014;11(1):10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Guérout N, Li X, Barnabé-Heider F. Cell fate control in the developing central nervous system. Exp Cell Res. 2014;321(1):77–83.

    Article  PubMed  CAS  Google Scholar 

  145. Fu H, Qi Y, Tan M, Cai J, Hu X, Liu Z, et al. Molecular mapping of the origin of postnatal spinal cord ependymal cells: evidence that adult ependymal cells are derived from Nkx6.1+ ventral neural progenitor cells. J Comp Neurol. 2003;456(3):237–44.

    Article  CAS  PubMed  Google Scholar 

  146. Spassky N, Merkle FT, Flames N, Tramontin AD, García-Verdugo JM, Alvarez-Buylla A. Adult ependymal cells are postmitotic and are derived from radial glial cells during embryogenesis. J Neurosci. 2005;25(1):10–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Yu K, McGlynn S, Matise MP. Floor plate-derived sonic hedgehog regulates glial and ependymal cell fates in the developing spinal cord. Development. 2013;140(7):1594–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Olstad EW, Ringers C, Hansen JN, Wens A, Brandt C, Wachten D, et al. Ciliary beating compartmentalizes cerebrospinal fluid flow in the brain and regulates ventricular development. Curr Biol. 2019;29(2):229–241.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Mirzadeh Z, Han Y-G, Soriano-Navarro M, Garcia-Verdugo JM, Alvarez-Buylla A. Cilia organize ependymal planar polarity. J Neurosci. 2010;30(7):2600–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Kishimoto N, Sawamoto K. Planar polarity of ependymal cilia. Differentiation. 2012;83(2):S86–90.

    Article  CAS  PubMed  Google Scholar 

  151. Lee L. Riding the wave of ependymal cilia: genetic susceptibility to hydrocephalus in primary ciliary dyskinesia. J Neurosci Res. 2013;91(9):1117–32.

    Article  CAS  PubMed  Google Scholar 

  152. Böhm UL, Prendergast A, Djenoune L, Nunes Figueiredo S, Gomez J, Stokes C, et al. CSF-contacting neurons regulate locomotion by relaying mechanical stimuli to spinal circuits. Nat Commun. 2016;7(1):10866.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Sternberg JR, Prendergast AE, Brosse L, Cantaut-Belarif Y, Thouvenin O, Orts-Del’Immagine A, et al. Pkd2l1 is required for mechanoception in cerebrospinal fluid-contacting neurons and maintenance of spine curvature. Nat Commun. 2018;9(1):3804.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Guertin PA. Central pattern generator for locomotion: anatomical, physiological, and pathophysiological considerations. Front Neurol. 2012;3:183.

    PubMed  Google Scholar 

  155. Fidelin K, Djenoune L, Stokes C, Prendergast A, Gomez J, Baradel A, et al. State-dependent modulation of locomotion by GABAergic spinal sensory neurons. Curr Biol. 2015;25(23):3035–47.

    Article  CAS  PubMed  Google Scholar 

  156. Van Gennip JLM, Boswell CW, Ciruna B. Neuroinflammatory signals drive spinal curve formation in zebrafish models of idiopathic scoliosis. Sci Adv. 2018;4(12):eaav1781.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Tracy MR, Dormans JP, Kusumi K. Klippel-Feil syndrome: clinical features and current understanding of etiology. Clin Orthop Relat Res. 2004;424:183–90.

    Article  Google Scholar 

  158. Mohamed JY, Faqeih E, Alsiddiky A, Alshammari MJ, Ibrahim NA, Alkuraya FS. Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly. Am J Hum Genet. 2013;92(1):157–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. McGaughran JM, Oates A, Donnai D, Read AP, Tassabehji M. Mutations in PAX1 may be associated with Klippel–Feil syndrome. Eur J Hum Genet. 2003;11(6):468–74.

    Article  CAS  PubMed  Google Scholar 

  160. Tassabehji M, Fang ZM, Hilton EN, McGaughran J, Zhao Z, de Bock CE, et al. Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome. Hum Mutat. 2008;29(8):1017–27.

    Article  CAS  PubMed  Google Scholar 

  161. Candia AF, Hu J, Crosby J, Lalley PA, Noden D, Nadeau JH, et al. Mox-1 and Mox-2 define a novel homeobox gene subfamily and are differentially expressed during early mesodermal patterning in mouse embryos. Development. 1992;116(4):1123–36.

    CAS  PubMed  Google Scholar 

  162. Mankoo BS, Skuntz S, Harrigan I, Grigorieva E, Candia A, Wright CVE, et al. The concerted action of Meox homeobox genes is required upstream of genetic pathways essential for the formation, patterning and differentiation of somites. Development. 2003;130(19):4655–64.

    Article  CAS  PubMed  Google Scholar 

  163. Candia AF, Wright CV. Differential localization of Mox-1 and Mox-2 proteins indicates distinct roles during development. Int J Dev Biol. 1996;40(6):1179–84.

    CAS  PubMed  Google Scholar 

  164. Skuntz S, Mankoo B, Nguyen M-TT, Hustert E, Nakayama A, Tournier-Lasserve E, et al. Lack of the mesodermal homeodomain protein MEOX1 disrupts sclerotome polarity and leads to a remodeling of the cranio-cervical joints of the axial skeleton. Dev Biol. 2009;332(2):383–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Mankoo BS, Collins NS, Ashby P, Grigorieva E, Pevny LH, Candia A, et al. Mox2 is a component of the genetic hierarchy controlling limb muscle development. Nature. 1999;400(6739):69–73.

    Article  CAS  PubMed  Google Scholar 

  166. Bayrakli F, Guclu B, Yakicier C, Balaban H, Kartal U, Erguner B, et al. Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype. BMC Genet. 2013;14(1):95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Mubarak AI, Morani AC. Anomalous vertebral arteries in Klippel-Feil syndrome with occipitalized atlas: CT angiography. Radiol Case Rep. 2018;13(2):434–6.

    Article  PubMed  PubMed Central  Google Scholar 

  168. Lettice LA, Purdie LA, Carlson GJ, Kilanowski F, Dorin J, Hill RE. The mouse bagpipe gene controls development of axial skeleton, skull, and spleen. Proc Natl Acad Sci U S A. 1999;96(17):9695–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Tribioli C, Lufkin T. The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen. Development. 1999;126(24):5699–711.

    CAS  PubMed  Google Scholar 

  170. Akazawa H, Komuro I, Sugitani Y, Yazaki Y, Nagai R, Noda T. Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation. Genes Cells. 2000;5(6):499–513.

    Article  CAS  PubMed  Google Scholar 

  171. Lettice L, Hecksher-Sørensen J, Hill R. The role of Bapx1 (Nkx3.2) in the development and evolution of the axial skeleton. J Anat. 2001;199(Pt 1–2):181–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Rodrigo I, Bovolenta P, Mankoo BS, Imai K. Meox homeodomain proteins are required for Bapx1 expression in the sclerotome and activate its transcription by direct binding to its promoter. Mol Cell Biol. 2004;24(7):2757–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Giampietro P, Raggio C, Reynolds C, Shukla S, McPherson E, Ghebranious N, et al. An analysis of PAX1 in the development of vertebral malformations. Clin Genet. 2005;68(5):448–53.

    Article  CAS  PubMed  Google Scholar 

  174. Peters H, Wilm B, Sakai N, Imai K, Maas R, Balling R. Pax1 and Pax9 synergistically regulate vertebral column development. Development. 1999;126(23):5399–408.

    CAS  PubMed  Google Scholar 

  175. Dauer MVP, Currie PD, Berger J. Skeletal malformations of Meox1-deficient zebrafish resemble human Klippel-Feil syndrome. J Anat. 2018;233(6):687–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Settle SH, 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.

    Article  CAS  PubMed  Google Scholar 

  177. Wei A, Shen B, Williams LA, Bhargav D, Gulati T, Fang Z, et al. Expression of growth differentiation factor 6 in the human developing fetal spine retreats from vertebral ossifying regions and is restricted to cartilaginous tissues. J Orthop Res. 2016;34(2):279–89.

    Article  CAS  PubMed  Google Scholar 

  178. Chen H, Capellini TD, Schoor M, Mortlock DP, Reddi AH, Kingsley DM. Heads, shoulders, elbows, knees, and toes: modular Gdf5 enhancers control different joints in the vertebrate skeleton. PLOS Genet. 2016;12(11):e1006454. Long F, editor.

    Article  PubMed  PubMed Central  Google Scholar 

  179. Isidor B, David A. Two girls with short stature, short neck, vertebral anomalies, Sprengel deformity and intellectual disability. Eur J Med Genet. 2015;58(1):47–50.

    Article  PubMed  Google Scholar 

  180. Wu N, Ming X, Xiao J, Wu Z, Chen X, Shinawi M, et al. TBX6 null variants and a common hypomorphic allele in congenital scoliosis. N Engl J Med. 2015;372(4):341–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Chapman DL, Papaioannou VE. Three neural tubes in mouse embryos with mutations in the T-box gene Tbx6. Nature. 1998;391(6668):695–7.

    Article  CAS  PubMed  Google Scholar 

  182. Chapman DL, Cooper-Morgan A, Harrelson Z, Papaioannou VE. Critical role for Tbx6 in mesoderm specification in the mouse embryo. Mech Dev. 2003;120(7):837–47.

    Article  CAS  PubMed  Google Scholar 

  183. Wittler L, Shin E, Grote P, Kispert A, Beckers A, Gossler A, et al. Expression of Msgn1 in the presomitic mesoderm is controlled by synergism of WNT signalling and Tbx6. EMBO Rep. 2007;8(8):784–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Takemoto T, Uchikawa M, Yoshida M, Bell DM, Lovell-Badge R, Papaioannou VE, et al. Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells. Nature. 2011;470(7334):394–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. White PH, Chapman DL. Dll1 is a downstream target of Tbx6 in the paraxial mesoderm. Genesis. 2005;42(3):193–202.

    Article  CAS  PubMed  Google Scholar 

  186. Yasuhiko Y, Haraguchi S, Kitajima S, Takahashi Y, Kanno J, Saga Y. Tbx6-mediated Notch signaling controls somite-specific Mesp2 expression. Proc Natl Acad Sci U S A. 2006;103(10):3651–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Oginuma M, Niwa Y, Chapman DL, Saga Y. Mesp2 and Tbx6 cooperatively create periodic patterns coupled with the clock machinery during mouse somitogenesis. Development. 2008;135(15):2555–62.

    Article  CAS  PubMed  Google Scholar 

  188. Gros J, Tabin CJ. Vertebrate limb bud formation is initiated by localized epithelial-to-mesenchymal transition. Science. 2014;343(6176):1253–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Nishimoto S, Wilde SM, Wood S, Logan MPO. RA acts in a coherent feed-forward mechanism with Tbx5 to control limb bud induction and initiation. Cell Rep. 2015;12(5):879–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Tanaka M, Zappavigna V, Conway SJ. Developmental mechanism of limb field specification along the anterior-posterior axis during vertebrate evolution. J Dev Biol. 2016;4(2):18.

    Article  PubMed Central  Google Scholar 

  191. Ng JK, Kawakami Y, Büscher D, Raya A, Itoh T, Koth CM, et al. The limb identity gene Tbx5 promotes limb initiation by interacting with Wnt2b and Fgf10. Development. 2002;129(22):5161–70.

    CAS  PubMed  Google Scholar 

  192. Agarwal P, Wylie JN, Galceran J, Arkhitko O, Li C, Deng C, et al. Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo. Development. 2003;130(3):623–33.

    Article  CAS  PubMed  Google Scholar 

  193. Naiche LA, Papaioannou VE. Tbx4 is not required for hindlimb identity or post-bud hindlimb outgrowth. Development. 2007;134(1):93–103.

    Article  CAS  PubMed  Google Scholar 

  194. Duboc V, Logan MPO. Pitx1 is necessary for normal initiation of hindlimb outgrowth through regulation of Tbx4 expression and shapes hindlimb morphologies via targeted growth control. Development. 2011;138(24):5301–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Kawakami Y, Marti M, Kawakami H, Itou J, Quach T, Johnson A, et al. Islet1-mediated activation of the B-catenin pathway is necessary for hindlimb initiation in mice. Development. 2011;138(20):4465–73.

    Google Scholar 

  196. Zuniga A. Next generation limb development and evolution: old questions, new perspectives. Development. 2015;142(22):3810–20.

    Article  CAS  PubMed  Google Scholar 

  197. Bénazet J-D, Zeller R. Vertebrate limb development: moving from classical morphogen gradients to an integrated 4-dimensional patterning system. Cold Spring Harb Perspect Biol. 2009;1(4):a001339.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Niswander L. Pattern formation: old models out on a limb. Nat Rev Genet. 2003;4(2):133–43.

    Article  CAS  PubMed  Google Scholar 

  199. Dreyer SD, Zhou G, Baldini A, Winterpacht A, Zabel B, Cole W, et al. Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet. 1998;19(1):47–50.

    Article  CAS  PubMed  Google Scholar 

  200. Sulaiman FA, Nishimoto S, Murphy GRF, Kucharska A, Butterfield NC, Newbury-Ecob R, et al. Tbx5 Buffers Inherent Left/Right Asymmetry Ensuring Symmetric Forelimb Formation. Barsh GS. PLOS Genet. 2016;12(12):e1006521.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Szenker-Ravi E, Altunoglu U, Leushacke M, Bosso-Lefèvre C, Khatoo M, Thi Tran H, et al. RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6. Nature. 2018;557(7706):564–9.

    Article  CAS  PubMed  Google Scholar 

  202. Lettice LA, Heaney SJ, Purdie LA, Li L, de Beer P, Oostra BA, et al. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet. 2003;12(14):1725–35.

    Article  CAS  PubMed  Google Scholar 

  203. Kvon EZ, Kamneva OK, Melo US, Barozzi I, Osterwalder M, Mannion BJ, et al. Progressive loss of function in a limb enhancer during snake evolution. Cell. 2016;167(3):633–642.e11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Ianakiev P, van Baren MJ, Daly MJ, Toledo SP, Cavalcanti MG, Neto JC, et al. Acheiropodia is caused by a genomic deletion in C7orf2, the human orthologue of the Lmbr1 gene. Am J Hum Genet. 2001;68(1):38–45.

    Article  CAS  PubMed  Google Scholar 

  205. Lettice LA, Hill AE, Devenney PS, Hill RE. Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly. Hum Mol Genet. 2008;17(7):978–85.

    Article  CAS  PubMed  Google Scholar 

  206. Blanc I, Bach A, Robert B. Unusual pattern of Sonic hedgehog expression in the polydactylous mouse mutant Hemimelic extra-toes. Int J Dev Biol. 2002;46(7):969–74.

    CAS  PubMed  Google Scholar 

  207. Riddle RD, Johnson RL, Laufer E, Tabin C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell. 1993;75(7):1401–16.

    Article  CAS  PubMed  Google Scholar 

  208. Harfe BD, Scherz PJ, Nissim S, Tian H, McMahon AP, Tabin CJ. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell. 2004;118(4):517–28.

    Article  CAS  PubMed  Google Scholar 

  209. Gurnett CA, Bowcock AM, Dietz FR, Morcuende JA, Murray JC, Dobbs MB. Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly. Am J Med Genet Part A. 2007;143A(1):27–32.

    Article  CAS  PubMed  Google Scholar 

  210. Lettice LA, Devenney P, De Angelis C, Hill RE. The conserved sonic Hedgehog limb enhancer consists of discrete functional elements that regulate precise spatial expression. Cell Rep. 2017;20(6):1396–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Hui CC, Joyner AL. A mouse model of greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nat Genet. 1993;3(3):241–6.

    Article  CAS  PubMed  Google Scholar 

  212. Vortkamp A, Gessler M, Grzeschik KH. GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature. 1991;352(6335):539–40.

    Article  CAS  PubMed  Google Scholar 

  213. Vortkamp A, Franz T, Gessler M, Grzeschik KH. Deletion of GLI3 supports the homology of the human Greig cephalopolysyndactyly syndrome (GCPS) and the mouse mutant extra toes (Xt). Mamm Genome. 1992;3(8):461–3.

    Article  CAS  PubMed  Google Scholar 

  214. Te Welscher P, Zuniga A, Kuijper S, Drenth T, Goedemans HJ, Meijlink F, et al. Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science. 2002;298(5594):827–30.

    Article  CAS  Google Scholar 

  215. Chiang C, Litingtung Y, Harris MP, Simandl BK, Li Y, Beachy PA, et al. Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. Dev Biol. 2001;236(2):421–35.

    Article  CAS  PubMed  Google Scholar 

  216. Sagai T. Elimination of a long-range cis-regulatory module causes complete loss of limb-specific Shh expression and truncation of the mouse limb. Development. 2005;132(4):797–803.

    Article  CAS  PubMed  Google Scholar 

  217. Barisic I, Boban L, Greenlees R, Garne E, Wellesley D, Calzolari E, et al. Holt Oram syndrome: a registry-based study in Europe. Orphanet J Rare Dis. 2014;9(1):156.

    Article  PubMed  PubMed Central  Google Scholar 

  218. McDermott DA, Fong JC, Basson CT. Holt-Oram syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle: University of Washington.

    Google Scholar 

  219. Wall LB, Piper SL, Habenicht R, Oishi SN, Ezaki M, Goldfarb CA. Defining features of the upper extremity in Holt-Oram syndrome. J Hand Surg Am. 2015;40(9):1764–8.

    Article  PubMed  PubMed Central  Google Scholar 

  220. Vanlerberghe C, Jourdain A-S, Ghoumid J, Frenois F, Mezel A, Vaksmann G, et al. Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants. Eur J Hum Genet. 2019;27(3):360–8.

    Article  CAS  PubMed  Google Scholar 

  221. Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis ARJ, Yi CH, et al. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet. 1997;15(1):21–9.

    Article  PubMed  Google Scholar 

  222. Basson CT, Huang T, Lin RC, Bachinsky DR, Weremowicz S, Vaglio A, et al. Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc Natl Acad Sci U S A. 1999;96(6):2919–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Bruneau BG, Nemer G, Schmitt JP, Charron F, Robitaille L, Caron S, et al. A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell. 2001;106(6):709–21.

    Article  CAS  PubMed  Google Scholar 

  224. Garrity DM, Childs S, Fishman MC. The heartstrings mutation in zebrafish causes heart/fin Tbx5 deficiency syndrome. Development. 2002;129(19):4635–45.

    CAS  PubMed  Google Scholar 

  225. Shi Z, Xin H, Tian D, Lian J, Wang J, Liu G, et al. Modeling human point mutation diseases in Xenopus tropicalis with a modified CRISPR/Cas9 system. FASEB J. 2019;fj.201802661R.

    Google Scholar 

  226. Yokoyama T, Copeland NG, Jenkins NA, Montgomery CA, Elder FF, Overbeek PA. Reversal of left-right asymmetry: a situs inversus mutation. Science. 1993;260(5108):679–82.

    Article  CAS  PubMed  Google Scholar 

  227. Tymowska J. Karyotype analysis of Xenopus tropicalis Gray, Pipidae. Cytogenet Genome Res. 1973;12(5):297–304.

    Article  CAS  Google Scholar 

  228. Tandon P, Conlon F, Furlow JD, Horb ME. Expanding the genetic toolkit in Xenopus: approaches and opportunities for human disease modeling. Dev Biol. 2017;426(2):325–35.

    Article  CAS  PubMed  Google Scholar 

  229. Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533(7603):420–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Niemann S. Tetra-Amelia syndrome. GeneReviews®. Seattle: University of Washington; 2007.

    Google Scholar 

  231. Niemann S, Zhao C, Pascu F, Stahl U, Aulepp U, Niswander L, et al. Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. Am J Hum Genet. 2004;74(3):558–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Barrow JR, Thomas KR, Boussadia-Zahui O, Moore R, Kemler R, Capecchi MR, et al. Ectodermal Wnt3/beta -catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. Genes Dev. 2003;17(3):394–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Sousa SB, Pina R, Ramos L, Pereira N, Krahn M, Borozdin W, et al. Tetra-amelia and lung hypo/aplasia syndrome: new case report and review. Am J Med Genet Part A. 2008;146A(21):2799–803.

    Article  PubMed  Google Scholar 

  234. Hao H-X, Xie Y, Zhang Y, Charlat O, Oster E, Avello M, et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature. 2012;485(7397):195–200.

    Article  CAS  PubMed  Google Scholar 

  235. Nam J-S, Park E, Turcotte TJ, Palencia S, Zhan X, Lee J, et al. Mouse R-spondin2 is required for apical ectodermal ridge maintenance in the hindlimb. Dev Biol. 2007;311(1):124–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Aoki M, Kiyonari H, Nakamura H, Okamoto H. R-spondin2 expression in the apical ectodermal ridge is essential for outgrowth and patterning in mouse limb development. Dev Growth Differ. 2007;50(2):85–95.

    Article  PubMed  Google Scholar 

  237. Bell SM, Schreiner CM, Wert SE, Mucenski ML, Scott WJ, Whitsett JA. R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis. Development. 2008;135(6):1049–58.

    Article  CAS  PubMed  Google Scholar 

  238. Yamada W, Nagao K, Horikoshi K, Fujikura A, Ikeda E, Inagaki Y, et al. Craniofacial malformation in R-spondin2 knockout mice. Biochem Biophys Res Commun. 2009;381(3):453–8.

    Article  CAS  PubMed  Google Scholar 

  239. Spielmann M, Lupiáñez DG, Mundlos S. Structural variation in the 3D genome. Nat Rev Genet. 2018;19(7):453–67.

    Article  CAS  PubMed  Google Scholar 

  240. Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485(7398):376–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009;326(5950):289–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Dekker J, Rippe K, Dekker M, Kleckner N. Capturing chromosome conformation. Science. 2002;295(5558):1306–11.

    Article  CAS  PubMed  Google Scholar 

  243. Simonis M, Klous P, Splinter E, Moshkin Y, Willemsen R, de Wit E, et al. Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture–on-chip (4C). Nat Genet. 2006;38(11):1348–54.

    Article  CAS  PubMed  Google Scholar 

  244. Zhao Z, Tavoosidana G, Sjölinder M, Göndör A, Mariano P, Wang S, et al. Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions. Nat Genet. 2006;38(11):1341–7.

    Article  CAS  PubMed  Google Scholar 

  245. de Wit E, de Laat W. A decade of 3C technologies: insights into nuclear organization. Genes Dev. 2012;26(1):11–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  246. Franke M, Ibrahim DM, Andrey G, Schwarzer W, Heinrich V, Schöpflin R, et al. Formation of new chromatin domains determines pathogenicity of genomic duplications. Nature. 2016;538(7624):265–9.

    Article  CAS  PubMed  Google Scholar 

  247. Kragesteen BK, Spielmann M, Paliou C, Heinrich V, Schöpflin R, Esposito A, et al. Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis. Nat Genet. 2018;50(10):1463–73.

    Article  CAS  PubMed  Google Scholar 

  248. Thiele H, McCann C, van’t Padje S, Schwabe GC, Hennies HC, Camera G, et al. Acropectorovertebral dysgenesis (F syndrome) maps to chromosome 2q36. J Med Genet. 2004;41(3):213–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Szeto DP, Rodriguez-Esteban C, Ryan AK, O’Connell SM, Liu F, Kioussi C, et al. Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes Dev. 1999;13(4):484–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Lanctôt C, Moreau A, Chamberland M, Tremblay ML, Drouin J. Hindlimb patterning and mandible development require the Ptx1 gene. Development. 1999;126(9):1805–10.

    PubMed  Google Scholar 

  251. Alvarado DM, McCall K, Aferol H, Silva MJ, Garbow JR, Spees WM, et al. Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice. Hum Mol Genet. 2011;20(20):3943–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Basit S, Khoshhal KI. Genetics of clubfoot; recent progress and future perspectives. Eur J Med Genet. 2018;61(2):107–13.

    Article  PubMed  Google Scholar 

  253. Gurnett CA, Alaee F, Kruse LM, Desruisseau DM, Hecht JT, Wise CA, et al. Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation. Am J Hum Genet. 2008;83(5):616–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Klopocki E, Kähler C, Foulds N, Shah H, Joseph B, Vogel H, et al. Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly. Eur J Hum Genet. 2012;20(6):705–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Minguillon C, Del Buono J, Logan MP. Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth. Dev Cell. 2005;8(1):75–84.

    Article  CAS  PubMed  Google Scholar 

  256. DeLaurier A, Schweitzer R, Logan M. Pitx1 determines the morphology of muscle, tendon, and bones of the hindlimb. Dev Biol. 2006;299(1):22–34.

    Article  CAS  PubMed  Google Scholar 

  257. Spielmann M, Brancati F, Krawitz PM, Robinson PN, Ibrahim DM, Franke M, et al. Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. Am J Hum Genet. 2012;91(4):629–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Al-Qattan MM, Al-Thunayan A, AlAbdulkareem I, Al Balwi M. Liebenberg syndrome is caused by a deletion upstream to the PITX1 gene resulting in transformation of the upper limbs to reflect lower limb characteristics. Gene. 2013;524(1):65–71.

    Article  CAS  PubMed  Google Scholar 

  259. Bianco S, Lupiáñez DG, Chiariello AM, Annunziatella C, Kraft K, Schöpflin R, et al. Polymer physics predicts the effects of structural variants on chromatin architecture. Nat Genet. 2018;50(5):662–7.

    Article  CAS  PubMed  Google Scholar 

  260. Kragesteen BK, Brancati F, Digilio MC, Mundlos S, Spielmann M. H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome. J Med Genet. 2019;56(4):246–51.

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Biological Sciences, University of Calgary, Calgary, AB, Canada

    Isabella Skuplik & John Cobb

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    Aimin Liu

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Skuplik, I., Cobb, J. (2020). Animal Models for Understanding Human Skeletal Defects. In: Liu, A. (eds) Animal Models of Human Birth Defects. Advances in Experimental Medicine and Biology, vol 1236. Springer, Singapore. https://doi.org/10.1007/978-981-15-2389-2_7

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