Genetic Regulation of Somite and Early Spinal Patterning

  • Kenro Kusumi
  • Walter Eckalbar
  • Olivier Pourquié


The spine plays an essential biomechanical role, and disruptions to the structure of the vertebral column can have profound clinical consequences. The structure of the spine is patterned early in embryonic development with the formation of transient segmental structures called somites. Developmental studies have helped to identify the genetic pathways regulating this process and the mutations that lead to severe congenital vertebral.


Retinoic Acid Fibroblast Growth Factor Notch Signaling Retinoic Acid Signaling Cycling Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to thank Mary-Lee Dequéant and Will Sewell for their contributions in preparing this chapter.


  1. Abu-Abed, S., Dollé, P., Metzger, D., Beckett, B., Chambon, P., and Petkovich, M. 2001. The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures. Genes Dev. 15:226–240.PubMedCrossRefGoogle Scholar
  2. Arnold, S.J. and Robertson, E.J. 2009. Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nat. Rev. Mol. Cell. Biol. 10:91–103.PubMedCrossRefGoogle Scholar
  3. Aulehla, A. and Johnson, R.L. 1999. Dynamic expression of lunatic fringe suggests a link between notch signaling and an autonomous cellular oscillator driving somite segmentation. Dev. Biol. 207:49–61.PubMedCrossRefGoogle Scholar
  4. Aulehla, A., Wehrle, C., Brand-Saberi, B., Kemler, R., Gossler, A., Kanzler, B., and Herrmann, B.G. 2003. Wnt3a plays a major role in the segmentation clock controlling somitogenesis. Dev. Cell 4:395–406.PubMedCrossRefGoogle Scholar
  5. Aulehla, A. and Herrmann, B.G. 2004. Segmentation in vertebrates: clock and gradient finally joined. Genes Dev. 18:2060–2067.PubMedCrossRefGoogle Scholar
  6. Aulehla, A., Wiegraebe, W., Baubet, V., Wahl, M.B., Deng, C., Taketo, M., Lewandoski, M., and Pourquié, O. 2008. A beta-catenin gradient links the clock and wavefront systems in mouse embryo segmentation. Nat. Cell Biol. 10:186–193.PubMedCrossRefGoogle Scholar
  7. Barrantes, I., Elia, A.J., Wünsch, K., Hrabe de Angelis, M.H., Mak, T.W., Rossant, J., Conlon, R.A., Gossler, A., and de la Pompa, J.L. 1999. Interaction between notch signalling and lunatic fringe during somite boundary formation in the mouse. Curr. Biol. 9:470–480.PubMedCrossRefGoogle Scholar
  8. Bessho, Y., Miyoshi, G., Sakata, R., and Kageyama, R. 2001a. Hes7: a bHLH-type repressor gene regulated by Notch and expressed in the presomitic mesoderm. Genes Cells 6:175–185.PubMedCrossRefGoogle Scholar
  9. Bessho, Y., Hirata, H., Masamizu, Y., and Kageyama, R. 2001b. Dynamic expression and essential functions of Hes7 in somite segmentation. Genes Dev. 15:2642–2647.PubMedCrossRefGoogle Scholar
  10. Bessho, Y., Hirata, H., Masamizu, Y., and Kageyama, R. 2003. Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock. Genes Dev. 17:1451–1456.PubMedCrossRefGoogle Scholar
  11. Bulman, M.P., Kusumi, K., Frayling, T.M., McKeown, C., Garrett, C., Lander, E.S., Krumlauf, R., Hattersley, A.T., Ellard, S., and Turnpenny, P.D. 2000. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat. Genet. 24:438–441.PubMedCrossRefGoogle Scholar
  12. Burgess, R., Cserjesi, P., Ligon, K.L., and Olson, E.N. 1995. Paraxis: a basic helix-loop-helix protein expressed in paraxial mesoderm and developing somites. Dev. Biol. 168:296–306.PubMedCrossRefGoogle Scholar
  13. Camenisch, T.D., Spicer, A.P., Brehm-Gibson, T., Biesterfeldt, J., Augustine, M.L., Calabro, A. Jr., Kubalak, S., Klewer, S.E., and McDonald, J.A. 2000. Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J. Clin. Invest. 106:349–360.PubMedCrossRefGoogle Scholar
  14. Chu, Y., Solski, P.A., Khosravi-Far, R., Der, C.J., and Kelly, K. 1996. The mitogen-activated protein kinase phosphatases PAC1, MKP-1, and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation. J. Biol. Chem. 271(11):6497–6501.PubMedCrossRefGoogle Scholar
  15. Ciruna, B. and Rossant, J. 2001. FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev. Cell 1(1):37–49.Google Scholar
  16. Cole, S.E., Levorse, J.M., Tilghman, S.M., and Vogt, T.F. 2002. Clock regulatory elements control cyclic expression of lunatic fringe during somitogenesis. Dev. Cell 3:75–84.PubMedCrossRefGoogle Scholar
  17. Conlon, R.A., Reaume, A.G., and Rossant, J. 1995. Notch1 is required for the coordinate segmentation of somites. Development. 121:1533–1545.PubMedGoogle Scholar
  18. Cooke, J. and Zeeman, E.C. 1976. A clock and wavefront model for control of the number of repeated structures during animal morphogenesis. J. Theor. Biol. 58:455–476.PubMedCrossRefGoogle Scholar
  19. Cooke, J. 1981. The problem of periodic patterns in embryos. Phil. Trans. R. Soc. Lond. B 295:509–524.CrossRefGoogle Scholar
  20. Cornier, A.S., Staehling-Hampton, K., Delventhal, K.M., Saga, Y., Caubet, J.F., Sasaki, N., Ellard, S., Young, E., Ramirez, N., Carlo, S.E., Torres, J., Emans, J.B., Turnpenny, P.D., and Pourquié, O. 2008. Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin syndrome. Am. J. Hum. Genet. 82(6):1334–1341.PubMedCrossRefGoogle Scholar
  21. Dale, J.K., Maroto, M., Dequéant, M.L., Malapert, P., McGrew, M., and Pourquié, O. 2003. Periodic notch inhibition by lunatic fringe underlies the chick segmentation clock. Nature 421:275–278.PubMedCrossRefGoogle Scholar
  22. Dale, J.K., Malapert, P., Chal, J., Vilhais-Neto, G., Maroto, M., Johnson, T., Jayasinghe, S., Trainor, P., Herrmann, B., and Pourquié. O. 2006. Oscillations of the snail genes in the presomitic mesoderm coordinate segmental patterning and morphogenesis in vertebrate somitogenesis. Dev. Cell 10:355–366.PubMedCrossRefGoogle Scholar
  23. Delfini, M.C., Dubrulle, J., Malapert, P., Chal, J., and Pourquie, O. 2005. Control of the segmentation process by graded MAPK/ERK activation in the chick embryo. Proc. Natl. Acad. Sci. U.S.A. 102:11343–11348.PubMedCrossRefGoogle Scholar
  24. Dequéant, M.L., Glynn, E., Gaudenz, K., Wahl, M., Chen, J., Mushegian, A., and Pourquié, O. 2006. A complex oscillating network of signaling genes underlies the mouse segmentation clock. Science 314:1595–1598.PubMedCrossRefGoogle Scholar
  25. Dequéant ML, and Pourquié O. 2008. Segmental patterning of the vertebrate embryonic axis. Nat. Rev. Genet. 9(5):370–382.PubMedCrossRefGoogle Scholar
  26. Diez del Corral, R., Olivera-Martinez, I., Goriely, A., Gale, E., Maden, M.,, and Storey, K. 2003. Opposing FGF and retinoid pathways control ventral neural pattern, neuronal differentiation, and segmentation during body axis extension. Neuron 40:65–79.PubMedCrossRefGoogle Scholar
  27. Duband, J.L., Dufour, S., Hatta, K., Takeichi, M., Edelman, G.M., and Thiery, J.P. 1987. Adhesion molecules during somitogenesis in the avian embryo. J. Cell Biol. 104:1361–1374.PubMedCrossRefGoogle Scholar
  28. Dubrulle, J., McGrew, M.J., and Pourquie, O. 2001. FGF signaling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation. Cell 106:219–232.PubMedCrossRefGoogle Scholar
  29. Dubrulle, J. and Pourquie, O. 2004a. fgf8 mRNA decay establishes a gradient that couples axial elongation to patterning in the vertebrate embryo. Nature 427:419–422.PubMedCrossRefGoogle Scholar
  30. Dubrulle, J. and Pourquie, O. 2004b. Coupling segmentation to axis formation. Development 131:5783–5793.PubMedCrossRefGoogle Scholar
  31. Dunty, W.C., Jr., Biris, K.K., Chalamalasetty, R.B., Taketo, M.M., Lewandoski, M., and Yamaguchi, T.P. 2008. Wnt3a/beta-catenin signaling controls posterior body development by coordinating mesoderm formation and segmentation. Development 135:85–94.PubMedCrossRefGoogle Scholar
  32. Dunwoodie, S.L., Clements, M., Sparrow, D.B., Sa, X., Conlon, R.A., and Beddington, R.S. 2002. 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 129:1795–1806.PubMedGoogle Scholar
  33. Eby, M.T., Jasmin, A., Kumar, A., Sharma, K., and Chaudhary, P.M. 2000. TAJ, a novel member of the tumor necrosis factor receptor family, activates the c-Jun N-terminal kinase pathway and mediates caspase-independent cell death. J. Biol. Chem. 275:15336–15342.PubMedCrossRefGoogle Scholar
  34. Elsdale, T., Pearson, M., and Whitehead, M. 1976. Abnormalities in somite segmentation following heat shock to Xenopus embryos. J. Embryol. Exp. Morphol. 35:625–635.PubMedGoogle Scholar
  35. Evrard, Y.A., Lun, Y., Aulehla, A., Gan, L., and Johnson, R.L. 1998. Lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 394:377–381.PubMedCrossRefGoogle Scholar
  36. Feng, X.-H., Liang, Y.-Y., Liang, M., Zhai, W., and Lin, X. 2002. Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-beta-mediated induction of the CDK inhibitor p15(Ink4B). Molec. Cell 9:133–143.PubMedCrossRefGoogle Scholar
  37. Forsberg, H., Crozet, F., and Brown, N.A. 1998. Waves of mouse Lunatic fringe expression, in four-hour cycles at two-hour intervals, precede somite boundary formation. Curr. Biol. 8:1027–1030.PubMedCrossRefGoogle Scholar
  38. Gessler, M., Knobeloch, K.P., Helisch, A., Amann, K., Schumacher, N., Rohde, E., Fischer, A., and Leimeister, C. 2002. Mouse gridlock: no aortic coarctation or deficiency, but fatal cardiac defects in Hey2 -/- mice. Curr. Biol. 12(18):1601–1604.PubMedCrossRefGoogle Scholar
  39. Gibb, S., Zagorska, A., Melton, K., Tenin, G., Vacca, I., Trainor, P., Maroto, M., and Dale, J.K. 2009 Interfering with Wnt signaling alters the periodicity of the segmentation clock. Dev. Biol. 330:21–31PubMedCrossRefGoogle Scholar
  40. Glinka, A., Wu, W., Delius, H., Monaghan, A.P., Blumenstock, C., and Niehrs, C. 1998. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 391:357–362.PubMedCrossRefGoogle Scholar
  41. Goldbeter, A., Gonze, D., and Pourquié, O. 2007. Sharp developmental thresholds defined through bistability by antagonistic gradients of retinoic acid and FGF signaling. Dev. Dyn. 236:1495–1508.PubMedCrossRefGoogle Scholar
  42. Goldman, D.C., Martin, G.R., and Tam, P.P. 2000. Fate and function of the ventral ectodermal ridge during mouse tail development. Development 127:2113–2123.PubMedGoogle Scholar
  43. Harrison, S.M., Houzelstein, D., Dunwoodie, S.L., and Beddington, R.S. 2000. Sp5, a new member of the Sp1 family, is dynamically expressed during development and genetically interacts with Brachyury. Dev. Biol. 227:358–372.PubMedCrossRefGoogle Scholar
  44. Hayashi, S., Shimoda, T., Nakajima, M., Tsukada, Y., Sakumura, Y., Dale, J.K., Maroto, M., Kohno, K., Matsui, T., and Bessho, Y. 2009. Sprouty4, an FGF inhibitor, displays cyclic gene expression under the control of the notch segmentation clock in the mouse PSM. PLOS. 4(5):e5603.Google Scholar
  45. He, T.C., Sparks, A.B., Rago, C., Hermeking, H., Zawel, L., da Costa, L.T., Morin, P.J., Vogelstein, B., and Kinzler, K.W. 1998. Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512.PubMedCrossRefGoogle Scholar
  46. Hirata, H., Yoshiura, S., Ohtsuka, T., Bessho, Y., Harada, T., Yoshikawa, K., and Kageyama, R. 2002. Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop. Science 298:840–843.PubMedCrossRefGoogle Scholar
  47. Hirata, H., Bessho, Y., Kokubu, H., Masamizu, Y., Yamada, S., Lewis, J., and Kageyama, R. 2004. Instability of Hes7 protein is crucial for the somite segmentation clock. Nat. Genet. 36:750–754.PubMedCrossRefGoogle Scholar
  48. Horikawa K, Radice G., Takeichi M, and Chisaka O. 1999. Adhesive subdivisions intrinsic to the epithelial somites. Dev. Biol. 215:182–189.PubMedCrossRefGoogle Scholar
  49. Hrabe de Angelis, M., McIntyre, J., 2nd, and Gossler, A. 1997. Maintenance of somite borders in mice requires the Delta homologue DII1. Nature 386:717–721.CrossRefGoogle Scholar
  50. Huppert, S.S., Ilagan, M.X., De Strooper, B., and Kopan, R. 2005. Analysis of Notch function in presomitic mesoderm suggests a gamma-secretase-independent role for presenilins in somite differentiation. Dev. Cell 8:677–688.PubMedCrossRefGoogle Scholar
  51. Ingalls, T.H. and Curley, F.J. 1957. Principles governing the genesis of congenital malformations induced in mice by hypoxia. N. Engl. J. Med. 257:1121–1127.PubMedCrossRefGoogle Scholar
  52. Ishibashi, M., Ang, S.L., Shiota, K., Nakanishi, S., Kageyama, R., and Guillemot, F. 1995. Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects. Genes Dev. 9:3136–3148.PubMedCrossRefGoogle Scholar
  53. Ishikawa, A., Kitajima, S., Takahashi, Y., Kokubo, H., Kanno, J., Inoue, T., and Saga Y. 2004. Mouse Nkd1, a Wnt antagonist, exhibits oscillatory gene expression in the PSM under the control of Notch signaling. Mech. Dev. 121:1443–1453.PubMedCrossRefGoogle Scholar
  54. Ishitani, T., Matsumoto, K., Chitnis, A.B., and Itoh, M. 2005. Nrarp functions to modulate neural-crest-cell differentiation by regulating LEF1 protein stability. Nat. Cell Biol. 7:1106–1112.PubMedCrossRefGoogle Scholar
  55. Jouve, C., Palmeirim, I., Henrique, D., Beckers, J., Gossler, A., Ish-Horowicz, D., and Pourquié, O. 2000. Notch signalling is required for cyclic expression of the hairy-like gene HES1 in the presomitic mesoderm. Development 127:1421–1429.PubMedGoogle Scholar
  56. Klock, A. and Herrmann, B.G. 2002. Cloning and expression of the mouse dual-specificity mitogen-activated protein (MAP) kinase phosphatase Mkp3 during mouse embryogenesis. Mech. Dev. 116(1–2):243–247.PubMedCrossRefGoogle Scholar
  57. Krebs, L.T., Deftos, M.L., Bevan, M.J., and Gridley, T. 2001. The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway. Dev. Biol. 238:110–119.PubMedCrossRefGoogle Scholar
  58. Kusumi, K., Sun, E.S., Kerrebrock, A.W., Bronson, R.T., Chi, D.C., Bulotsky, M.S., Spencer, J.B., Birren, B.W., Frankel, W.N., and Lander, E.S. 1998. The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries. Nat. Genet. 19(3):274–278.PubMedCrossRefGoogle Scholar
  59. Kusumi, K., Mimoto, M.S., Covello, K.L., Beddington, R.S., Krumlauf, R., and Dunwoodie, S.L. 2004. Dll3 pudgy mutation differentially disrupts dynamic expression of somite genes. Genesis 39(2):115–121.PubMedCrossRefGoogle Scholar
  60. Lamar, E., Deblandre, G., Wettstein, D., Gawantka, V., Pollet, N., Niehrs, C., and Kintner, C. 2001. Nrarp is a novel intracellular component of the Notch signaling pathway. Genes Dev. 15:1885–1899.PubMedCrossRefGoogle Scholar
  61. Leimeister, C., Dale, K., Fischer, A., Klamt, B., Hrabe de Angelis, M., Radtke, F., McGrew, M.J., Pourquié, O., and Gessler, M. 2000a. Oscillating expression of c-hey2 in the presomitic mesoderm suggests that the segmentation clock may use combinatorial signaling through multiple interacting bHLH factors. Dev. Biol. 227:91–103.PubMedCrossRefGoogle Scholar
  62. Leimeister, C., Schumacher, N., Steidl, C., and Gessler, M. 2000b. Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos. Mech. Dev. 98(1–2):175–178.PubMedCrossRefGoogle Scholar
  63. Lewis, J. 2003. Autoinhibition with transcriptional delay: a simple mechanism for the zebrafish somitogenesis oscillator. Curr. Biol. 13(16):1398–1408.PubMedCrossRefGoogle Scholar
  64. Linask, K.K., Ludwig, C., Han, M.D., Liu, X., Radice, G.L., and Knudsen, K.A. 1998. N-cadherin/catenin-mediated morphoregulation of somite formation. Dev. Biol. 202:85–102.PubMedCrossRefGoogle Scholar
  65. Loder, R.T., Hernandez, M.J., Lerner, A.L., Winebrener, D.J., Goldstein, S.A., Hensinger, R.N., Liu, C.Y., and Schork, M.A. 2000. The induction of congenital spinal deformities in mice by maternal carbon monoxide exposure. J. Pediatr. Orthop. 20:662–666.PubMedGoogle Scholar
  66. MacDonald, B.T., Adamska, M., and Meisler, M.H. 2004. Hypomorphic expression of Dkk1 in the doubleridge mouse: dose dependence and compensatory interactions with Lrp6. Development. 131:2543–2552.PubMedCrossRefGoogle Scholar
  67. McGrew, M.J., Dale, J.K., Fraboulet, S., and Pourquié, O. 1998. The lunatic fringe gene is a target of the molecular clock linked to somite segmentation in avian embryos. Curr. Biol. 8:979–982.PubMedCrossRefGoogle Scholar
  68. Monk, N.A.M. 2003. Oscillatory expression of Hes1, p53 and NF-kB driven by transcriptional time delays. Curr. Biol. 13:1409–1413.PubMedCrossRefGoogle Scholar
  69. Morales, A.V., Yasuda, Y., and Ish-Horowicz, D. 2002. Periodic lunatic fringe expression is controlled during segmentation by a cyclic transcriptional enhancer responsive to notch signaling. Dev. Cell 3:63–74.PubMedCrossRefGoogle Scholar
  70. Moreno, T.A. and Kintner, C. 2004. Regulation of segmental patterning by retinoic acid signaling during Xenopus somitogenesis. Dev. Cell 6:205–218.PubMedCrossRefGoogle Scholar
  71. Morimoto, M., Takahashi, Y., Endo, M., and Saga, Y. 2005. The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity. Nature 435:354–359.PubMedCrossRefGoogle Scholar
  72. Murakami, U. and Kameyama, Y. 1963. Vertebral malformations in the mouse fetus caused by maternal hypoxia during early stages of pregnancy. J. Embryol. Exp. Morphol. 11: 107–118.Google Scholar
  73. Murray, F.J., Schwetz, B.A., Crawford, A.A., Henck, J.W., Quast, J.F., and Staples, R.E. 1979. Embryotoxicity of inhaled sulfur dioxide and carbon monoxide in mice and rabbits. J. Environ. Sci. Health 13:233–250.Google Scholar
  74. Nakaya, M.A., Biris, K., Tsukiyama, T., Jaime, S., Rawls, J.A., and Yamaguchi, T.P. 2005. Wnt3a links left-right determination with segmentation and anteroposterior axis elongation. Development 132:5425–5436.PubMedCrossRefGoogle Scholar
  75. Nakaya, Y., Kuroda, S., Katagiri, Y.T., Kaibuchi, K., and Takahashi, Y. 2004. Mesenchymal-epithelial transition during somitic segmentation is regulated by differential roles of Cdc42 and Rac1. Dev Cell 7:425–438.PubMedCrossRefGoogle Scholar
  76. National Center for Health Statistics. 2009. Health, United States, 2008 with Chartbook. Hyattsville, MD: U.S. Department of Health and Human Services.Google Scholar
  77. Niederreither, K., Fraulob, V., Garnier, J.M., Chambon, P., and Dolle, P. 2002a. Differential expression of retinoic acid-synthesizing (RALDH) enzymes during fetal development and organ differentiation in the mouse. Mech. Dev. 110:165–171.PubMedCrossRefGoogle Scholar
  78. Niederreither, K., Abu-Abed, S., Schuhbaur, B., Petkovich, M., Chambon, P., and Dollé, P. 2002b. Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development. Nat. Genet. 31:84–88.PubMedGoogle Scholar
  79. Niwa, Y., Masamizu, Y., Liu, T., Nakayama, R., Deng, C.X., and Kageyama, R. 2007. The initiation and propagation of Hes7 oscillation are cooperatively regulated by Fgf and notch signaling in the somite segmentation clock. Dev. Cell 13:298–304.PubMedCrossRefGoogle Scholar
  80. Ohtsuka, T., Ishibashi, M., Gradwohl, G., Nakanishi, S., Guillemot, F., and Kageyama, R. 1999. Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation. EMBO J. 18:2196–2207.PubMedCrossRefGoogle Scholar
  81. Oka, C., Nakano, T., Wakeham, A., de la Pompa, J.L., Mori, C., Sakai, T., Okazaki, S., Kawaichi, M., Shiota, K., Mak, T.W., and Honjo, T. 1995. Disruption of the mouse RBP-J kappa gene results in early embryonic death. Development. 121(10):3291–3301.PubMedGoogle Scholar
  82. O’Rahilly, R., Muller, F., and Meyer, D.B. 1980. The human vertebral column at the end of the embryonic period proper. 1. The column as a whole. J. Anat. 131(Pt 3):565–575.PubMedGoogle Scholar
  83. Palmeirim, I., Henrique, D., Ish-Horowicz, D., and Pourquié, O. 1997. Avian hairy gene expression identifies a molecular clock linked to vertebrate segmentation and somitogenesis. Cell 91:639–648.PubMedCrossRefGoogle Scholar
  84. Perantoni, A.O., Timofeeva, O., Naillat, F., Richman, C., Pajni-Underwood, S., Wilson, C., Vainio, S., Dove, L.F., and Lewandoski, M. 2005. Inactivation of FGF8 in early mesoderm reveals an essential role in kidney development. Development 132:3859–3871.PubMedCrossRefGoogle Scholar
  85. Pirot, P., van Grunsven, L.A., Marine, J.C., Huylebroeck, D., and Bellefroid, E.J. 2004. Direct regulation of the Nrarp gene promoter by the Notch signaling pathway. Biochem. Biophys. Res. Commun. 322:526–534.PubMedCrossRefGoogle Scholar
  86. Pourquié, O., and Tam, P.P. 2001. A nomenclature for prospective somites and phases of cyclic gene expression in the presomitic mesoderm. Dev. Cell 1:619–620.PubMedCrossRefGoogle Scholar
  87. Rivard, C.H., Narbaitz, R., and Uhthoff, H.K. 1979. Time of induction of congenital vertebral malformations in human and mouse embryo. Orthop. Rev. 8:135–139.Google Scholar
  88. Saga, Y. and Takeda, H. 2001. The making of the somite: molecular events in vertebrate segmentation. Nat. Rev. Genet. 2:835–845.PubMedCrossRefGoogle Scholar
  89. Sansom, O.J., Meniel, V.S., Muncan, V., Phesse, T.J., Wilkins, J.A., Reed, K.R., Vass, J.K., Athineos, D., Clevers, H., and Clarke, A.R. 2007. Myc deletion rescues Apc deficiency in the small intestine. Nature 446:676–679.PubMedCrossRefGoogle Scholar
  90. Sawada, A., Shinya, M., Jiang, Y.J., Kawakami, A., Kuroiwa, A., and Takeda, H. 2001. Fgf/MAPK signalling is a crucial positional cue in somite boundary formation. Development. 128:4873–4880.PubMedGoogle Scholar
  91. Saxton, T.M. and Pawson, T. 1999. Morphogenetic movements at gastrulation require the SH2 tyrosine phosphatase Shp2. Proc. Natl. Acad. Sci. U.S.A. 96(7):3790–3795.PubMedCrossRefGoogle Scholar
  92. Schuster-Gossler, K., Harris, B., Johnson, K.R., Serth, J., and Gossler, A. 2009. Notch signalling in the paraxial mesoderm is most sensitive to reduced Pofut1 levels during early mouse development. BMC Dev. Biol. 9:6.PubMedCrossRefGoogle Scholar
  93. Schwetz, B.A., Smith, F.A., Leong, B.K.J., and Staples, R.E. 1979. Teratogenic potential of inhaled carbon monoxide in mice and rabbits. Teratology 19:385–392.PubMedCrossRefGoogle Scholar
  94. Serth, K., Schuster-Gossler, K., Cordes, R., and Gossler, A. 2003. Transcriptional oscillation of Lunatic fringe is essential for somitogenesis. Genes Dev. 17:912–925.PubMedCrossRefGoogle Scholar
  95. Sewell, W., Sparrow, D., Gonzalez, D.M., Smith, A., Eckalbar, W., Gibson, J., Dunwoodie, S.L., and Kusumi, K. 2009. Cyclical expression of the Notch/Wnt regulator Nrarp requires Dll3 function in somitogenesis. Dev Biol. 329:400–409.PubMedCrossRefGoogle Scholar
  96. Sharma, B., Handler, M., Eichstetter, I., Whitelock, J.M., Nugent, M.A., and Iozzo, R.V. 1998. Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo. J. Clin. Invest. 102:1599–1608.PubMedCrossRefGoogle Scholar
  97. Shen, J., Bronson, R.T., Chen, D.F., Xia, W., Selkoe, D.J., and Tonegawa, S. 1997. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 89:629–639.PubMedCrossRefGoogle Scholar
  98. Shifley, E.T., Vanhorn, K.M., Perez-Balaguer, A., Franklin, J.D., Weinstein, M., and Cole, S.E. 2008. Oscillatory lunatic fringe activity is crucial for segmentation of the anterior but not posterior skeleton. Development 135:899–908.PubMedCrossRefGoogle Scholar
  99. Shim, K., Minowada, G., Coling, D.E., and Martin, G.R. 2005. Sprouty2, a mouse deafness gene, regulates cell fate decisions in the auditory sensory epithelium by antagonizing FGF signaling. Dev. Cell 8:553–564.PubMedCrossRefGoogle Scholar
  100. Singh, J., Aggison, L., and Moore-Cheatum, L. 1984. Teratogenicity and developmental toxicity of carbon monoxide in protein deficient mice. Teratology 48:149–159.CrossRefGoogle Scholar
  101. Sirbu, I.O. and Duester, G. 2006. Retinoic-acid signaling in node ectoderm and posterior neural plate directs left-right patterning of somitic mesoderm. Nat. Cell Biol. 8:271–277.PubMedCrossRefGoogle Scholar
  102. Sparrow, D.B., Chapman, G., Wouters, M.A., Whittock, N.V., Ellard, S., Fatkin, D., Turnpenny, P.D., Kusumi, K., Sillence, D., and Dunwoodie, S.L. 2006. Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am. J. Hum. Genet. 78:28–37.PubMedCrossRefGoogle Scholar
  103. Sparrow, D.B., Guillén-Navarro, E., Fatkin, D., and Dunwoodie, S.L. 2008. Mutation of hairy-and-enhancer-of-split-7 in humans causes spondylocostal dysostosis. Hum. Mol. Genet. 17(23):3761–3766.PubMedCrossRefGoogle Scholar
  104. Suriben, R., Fisher, D.A., and Cheyette, B.N. 2006. Dact1 presomitic mesoderm expression oscillates in phase with Axin2 in the somitogenesis clock of mice. Dev. Dyn. 235(11):3177–3183.PubMedCrossRefGoogle Scholar
  105. Tam, P.P. and Tan, S.S. 1992. The somatogenetic potential of cells in the primitive streak and the tail bud of the organogenesis-stage mouse embryo. Development 115:703–715.PubMedGoogle Scholar
  106. Trumpp, A., Refaeli, Y., Oskarsson, T., Gasser, S., Murphy, M., Martin, G.R., and Bishop, J.M. 2001. c-Myc regulates mammalian body size by controlling cell number but not cell size. Nature 414:768–773.PubMedCrossRefGoogle Scholar
  107. Vermot, J. and Pourquie, O. 2005. Retinoic acid coordinates somitogenesis and left-right patterning in vertebrate embryos. Nature 435:215–220.PubMedCrossRefGoogle Scholar
  108. Wahl, M.B., Deng, C., Lewandoski, M., and Pourquie, O. 2007. FGF signaling acts upstream of the NOTCH and WNT signaling pathways to control segmentation clock oscillations in mouse somitogenesis. Development 134:4033–4041.PubMedCrossRefGoogle Scholar
  109. Weidinger, G., Thorpe, C.J., Wuennenberg-Stapleton, K., Ngai, J., and Moon, R.T. 2005. The Sp1-related transcription factors sp5 and sp5-like act downstream of Wnt/beta-catenin signaling in mesoderm and neuroectoderm patterning. Curr. Biol. 15:489–500.PubMedCrossRefGoogle Scholar
  110. Whittock, N.V., Sparrow, D.B., Wouters, M.A., Sillence, D., Ellard, S., Dunwoodie, S.L., and Turnpenny, P.D. 2004. Mutated MESP2 causes spondylocostal dysostosis in humans. Am. J. Hum. Genet. 74:1249–1254.PubMedCrossRefGoogle Scholar
  111. William, D.A., Saitta, B., Gibson, J.D., Traas, J., Markov, V., Gonzalez, D.M., Sewell, W., Anderson, D.M., Pratt, S.C., Rappaport, E.F., and Kusumi, K. 2007. Identification of oscillatory genes in somitogenesis from functional genomic analysis of a human mesenchymal stem cell model. Dev. Biol. 305:172–186.PubMedCrossRefGoogle Scholar
  112. Wilson, V. and Beddington, R.S. 1996. Cell fate and morphogenetic movement in the late mouse primitive streak. Mech. Dev. 55:79–89.PubMedCrossRefGoogle Scholar
  113. Yu, H.M., Jerchow, B., Sheu, T.J., Liu, B., Costantini, F., Puzas, J.E., Birchmeier, W., and Hsu, W. 2005. The role of Axin2 in calvarial morphogenesis and craniosynostosis. Development 132:1995–2005.PubMedCrossRefGoogle Scholar
  114. Zhang, N., and Gridley, T. 1998. Defects in somite formation in lunatic fringe-deficient mice. Nature. 394:374–377.PubMedCrossRefGoogle Scholar
  115. Zhang, S., Cagatay, T., Amanai, M., Zhang, M., Kline, J., Castrillon, D.H., Ashfaq, R., Oz, O.K., and Wharton, K.A. Jr. 2007. Viable mice with compound mutations in the Wnt/Dvl pathway antagonists nkd1 and nkd2. Mol. Cell. Biol. 27(12):4454–4464.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.School of Life SciencesArizona State UniversityTempeUSA
  2. 2.Department of Basic Medical SciencesThe University of Arizona College of Medicine–Phoenix in Partnership with Arizona State UniversityPhoenixUSA
  3. 3.Département de Biologie Cellulaire et DéveloppementIGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire)IllkirchFrance
  4. 4.Inserm, U964IllkirchFrance
  5. 5.CNRS, UMR7104IllkirchFrance
  6. 6.Université de StrasbourgStrasbourgFrance

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