Skip to main content
SpringerLink
Log in

Genetics and Developmental Biology of Closed Dysraphic Conditions

  • Chapter
  • First Online:
Occult Spinal Dysraphism

Abstract

Closed spinal dysraphic conditions are typically considered malformations of caudal development and have prompted intense speculation on possible pathogenic mechanisms. Ultimately, an understanding of developmental processes, both normal and abnormal, requires an experimental evidence base. This chapter surveys the experimental literature for clues to the genetics and developmental biology of human spinal dysraphism, based largely on studies in mouse models. Current trends in human disease gene identification, and the development of mouse genetic disease models are reviewed, as well as several key areas of developmental biology progress that relate to development of the caudal body axis. Open neural tube defects (e.g. myelomeningocele) are relatively well understood owing to the many mouse models of faulty neural tube closure. Closed lesions in which the spinal cord is tethered and associated with spinal lipoma are much less well represented in mouse models; only preliminary clues to their likely developmental origins can currently be discerned. Some closed sacro-caudal conditions have a more defined genetic and developmental biology basis, for example dorsal and ventral vertebral anomalies, caudal regression syndrome and Currarino triad. A future concerted research effort is needed to bring together clinical observations with research in developmental biology in this important area of paediatric clinical management.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Webber DM, MacLeod SL, Bamshad MJ, Shaw GM, Finnell RH, Shete SS, Witte JS, Erickson SW, Murphy LD, Hobbs C. Developments in our understanding of the genetic basis of birth defects. Birth Defects Res A Clin Mol Teratol. 2015;103:680–91.

    Article  CAS  Google Scholar 

  2. Robinson A, Escuin S, Doudney K, Vekemans M, Stevenson RE, Greene ND, Copp AJ, Stanier P. Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis. Hum Mutat. 2012;33:440–7.

    Article  CAS  Google Scholar 

  3. Narisawa A, Komatsuzaki S, Kikuchi A, Niihori T, Aoki Y, Fujiwara K, Tanemura M, Hata A, Suzuki Y, Relton CL, Grinham J, Leung KY, Partridge D, Robinson A, Stone V, Gustavsson P, Stanier P, Copp AJ, Greene ND, Tominaga T, Matsubara Y, Kure S. Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans. Hum Mol Genet. 2012;21:1496–503.

    Article  CAS  Google Scholar 

  4. Tschaharganeh DF, Lowe SW, Garippa RJ, Livshits G. Using CRISPR/Cas to study gene function and model disease in vivo. FEBS J. 2016;283:3194–203.

    Article  CAS  Google Scholar 

  5. Melton DW. Gene targeting in the mouse. BioEssays. 1994;16:633–8.

    Article  CAS  Google Scholar 

  6. Juriloff DM, Harris MJ. Mouse models for neural tube closure defects. Hum Mol Genet. 2000;9:993–1000.

    Article  CAS  Google Scholar 

  7. Harris MJ, Juriloff DM. An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure. Birth Defects Res A Clin Mol Teratol. 2010;88:653–69.

    Article  CAS  Google Scholar 

  8. Gouti M, Metzis V, Briscoe J. The route to spinal cord cell types: a tale of signals and switches. Trends Genet. 2015;31:282–9.

    Article  CAS  Google Scholar 

  9. Tzouanacou E, Wegener A, Wymeersch FJ, Wilson V, Nicolas JF. Redefining the progression of lineage segregations during mammalian embryogenesis by clonal analysis. Dev Cell. 2009;17:365–76.

    Article  CAS  Google Scholar 

  10. Henrique D, Abranches E, Verrier L, Storey KG. Neuromesodermal progenitors and the making of the spinal cord. Development. 2015;142:2864–75.

    Article  CAS  Google Scholar 

  11. Gouti M, Tsakiridis A, Wymeersch FJ, Huang Y, Kleinjung J, Wilson V, Briscoe J. In vitro generation of neuromesodermal progenitors reveals distinct roles for wnt signalling in the specification of spinal cord and paraxial mesoderm identity. PLoS Biol. 2014;12:e1001937.

    Article  Google Scholar 

  12. Tissir F, Goffinet AM. Planar cell polarity signaling in neural development. Curr Opin Neurobiol. 2010;20:572–7.

    Article  CAS  Google Scholar 

  13. Ybot-Gonzalez P, Savery D, Gerrelli D, Signore M, Mitchell CE, Faux CH, Greene NDE, Copp AJ. Convergent extension, planar-cell-polarity signalling and initiation of mouse neural tube closure. Development. 2007;134:789–99.

    Article  CAS  Google Scholar 

  14. Copp AJ, Greene NDE, Murdoch JN. The genetic basis of mammalian neurulation. Nat Rev Genet. 2003;4:784–93.

    Article  Google Scholar 

  15. Schoenwolf GC. Histological and ultrastructural studies of secondary neurulation of mouse embryos. Am J Anat. 1984;169:361–74.

    Article  CAS  Google Scholar 

  16. Graham A. The neural crest. Curr Biol. 2003;13:R381–4.

    Article  CAS  Google Scholar 

  17. Catala M, Ziller C, Lapointe F, Le Douarin NM. The developmental potentials of the caudalmost part of the neural crest are restricted to melanocytes and glia. Mech Dev. 2000;95:77–87.

    Article  CAS  Google Scholar 

  18. Pourquié O. The segmentation clock: converting embryonic time into spatial pattern. Science. 2003;301:328–30.

    Article  Google Scholar 

  19. Christ B, Wilting J. From somites to vertebral column. Ann Anat. 1992;174:23–32.

    Article  CAS  Google Scholar 

  20. Kwon GS, Viotti M, Hadjantonakis AK. The endoderm of the mouse embryo arises by dynamic widespread intercalation of embryonic and extraembryonic lineages. Dev Cell. 2008;15:509–20.

    Article  CAS  Google Scholar 

  21. Müller F, O’Rahilly R. The primitive streak, the caudal eminence and related structures in staged human embryos. Cells Tissues Organs. 2004;177:2–20.

    Article  Google Scholar 

  22. Yamanaka Y, Tamplin OJ, Beckers A, Gossler A, Rossant J. Live imaging and genetic analysis of mouse notochord formation reveals regional morphogenetic mechanisms. Dev Cell. 2007;13:884–96.

    Article  CAS  Google Scholar 

  23. Lawson LY, Harfe BD. Developmental mechanisms of intervertebral disc and vertebral column formation. Wiley Interdiscip Rev Dev Biol. 2017;6:e283.

    Article  Google Scholar 

  24. O’Rahilly R, Müller F. The two sites of fusion of the neural folds and the two neuropores in the human embryo. Teratology. 2002;65:162–70.

    Article  Google Scholar 

  25. Sakai Y. Neurulation in the mouse: manner and timing of neural tube closure. Anat Rec. 1989;223:194–203.

    Article  CAS  Google Scholar 

  26. Golden JA, Chernoff GF. Intermittent pattern of neural tube closure in two strains of mice. Teratology. 1993;47:73–80.

    Article  CAS  Google Scholar 

  27. Van Allen MI, Kalousek DK, Chernoff GF, Juriloff D, Harris M, McGillivray BC, Yong S-L, Langlois S, MacLeod PM, Chitayat D, Friedman JM, Wilson RD, McFadden D, Pantzar J, Ritchie S, Hall JG. Evidence for multi-site closure of the neural tube in humans. Am J Med Genet. 1993;47:723–43.

    Article  Google Scholar 

  28. Juriloff DM, Harris MJ. A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects. Birth Defects Res A Clin Mol Teratol. 2012;94:824–40.

    Article  CAS  Google Scholar 

  29. Shah RH, Northrup H, Hixson JE, Morrison AC, Au KS. Genetic association of the glycine cleavage system genes and myelomeningocele. Birth Defects Res A Clin Mol Teratol. 2016;106:847–53.

    Article  CAS  Google Scholar 

  30. Pai YJ, Leung KY, Savery D, Hutchin T, Prunty H, Heales S, Brosnan ME, Brosnan JT, Copp AJ, Greene ND. Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice. Nat Commun. 2015;6:6388.

    Article  CAS  Google Scholar 

  31. Wilson V, Olivera-Martinez I, Storey KG. Stem cells, signals and vertebrate body axis extension. Development. 2009;136:1591–604.

    Article  CAS  Google Scholar 

  32. Arthurs OJ, Thayyil S, Wade A, Chong WK, Sebire NJ, Taylor AM. Normal ascent of the conus medullaris: a post-mortem foetal MRI study. J Matern Fetal Neonatal Med. 2013;26:697–702.

    Article  CAS  Google Scholar 

  33. Stiefel D, Shibata T, Meuli M, Duffy P, Copp AJ. Tethering of the spinal cord in mouse fetuses and neonates with spina bifida. J Neurosurg Spine. 2003;99:206–13.

    Article  Google Scholar 

  34. Griffith CM, Wiley MJ, Sanders EJ. The vertebrate tail bud: three germ layers from one tissue. Anat Embryol. 1992;185:101–13.

    Article  CAS  Google Scholar 

  35. Eibach S, Moes G, Hou YJ, Zovickian J, Pang D. Unjoined primary and secondary neural tubes: junctional neural tube defect, a new form of spinal dysraphism caused by disturbance of junctional neurulation. Childs Nerv Syst. 2016;33:1633–47.

    Article  Google Scholar 

  36. Schmidt C, Voin V, Iwanaga J, Alonso F, Oskouian RJ, Topale N, Tubbs RS, Oakes WJ. Junctional neural tube defect in a newborn: report of a fourth case. Childs Nerv Syst. 2017;33:873–5.

    Article  Google Scholar 

  37. Dady A, Havis E, Escriou V, Catala M, Duband JL. Junctional neurulation: a unique developmental program shaping a discrete region of the spinal cord highly susceptible to neural tube defects. J Neurosci. 2014;34:13208–21.

    Article  Google Scholar 

  38. Schoenwolf GC, De Longo J. Ultrastructure of secondary neurulation in the chick embryo. Am J Anat. 1980;158:43–63.

    Article  CAS  Google Scholar 

  39. Liu C, Lin C, Gao C, May-Simera H, Swaroop A, Li T. Null and hypomorph Prickle1 alleles in mice phenocopy human Robinow syndrome and disrupt signaling downstream of Wnt5a. Biol Open. 2014;3:861–70.

    Article  CAS  Google Scholar 

  40. Nait-Oumesmar B, Stecca B, Fatterpekar G, Naidich T, Corbin J, Lazzarini RA. Ectopic expression of Gcm1 induces congenital spinal cord abnormalities. Development. 2002;129:3957–64.

    CAS  PubMed  Google Scholar 

  41. Hitoshi S, Ishino Y, Kumar A, Jasmine S, Tanaka KF, Kondo T, Kato S, Hosoya T, Hotta Y, Ikenaka K. Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells. Nat Neurosci. 2011;14:957–64.

    Article  CAS  Google Scholar 

  42. Naidich TP, McLone DG, Mutluer S. A new understanding of dorsal dysraphism with lipoma (lipomyeloschisis): radiologic evaluation and surgical correction. AJR Am J Roentgenol. 1983;140:1065–78.

    Article  CAS  Google Scholar 

  43. Li YC, Shin SH, Cho BK, Lee MS, Lee YJ, Hong SK, Wang KC. Pathogenesis of lumbosacral lipoma: a test of the ‘premature dysjunction’ theory. Pediatr Neurosurg. 2001;34:124–30.

    Article  CAS  Google Scholar 

  44. Tam PPL. The histogenetic capacity of tissues in the caudal end of the embryonic axis of the mouse. J Embryol Exp Morpholog. 1984;82:253–66.

    CAS  Google Scholar 

  45. Oliveria SF, Thompson EM, Selden NR. Lumbar lipomyelomeningocele and sacrococcygeal teratoma in siblings: support for an alternative theory of spinal teratoma formation. J Neurosurg Pediatr. 2010;5:626–9.

    Article  Google Scholar 

  46. 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;237:3953–8.

    Article  CAS  Google Scholar 

  47. Yang XR, Ng D, Alcorta DA, Liebsch NJ, Sheridan E, Li S, Goldstein AM, Parry DM, Kelley MJ. T (brachyury) gene duplication confers major susceptibility to familial chordoma. Nat Genet. 2009;41:1176–8.

    Article  CAS  Google Scholar 

  48. Vujovic S, Henderson S, Presneau N, Odell E, Jacques TS, Tirabosco R, Boshoff C, Flanagan AM. Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol. 2006;209:157–65.

    Article  CAS  Google Scholar 

  49. Stevenson RE, Jones KL, Phelan MC, Jones MC, Barr M Jr, Clericuzio C, Harley RA, Benirschke K. Vascular steal: the pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics. 1986;78:451–7.

    CAS  PubMed  Google Scholar 

  50. Abu-Abed S, Dollé P, Metzger D, Beckett B, Chambon P, Petkovich M. The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures. Genes Dev. 2001;15:226–40.

    Article  CAS  Google Scholar 

  51. Lee LM, Leung MB, Kwok RC, Leung YC, Wang CC, McCaffery PJ, Copp AJ, Shum AS. Perturbation of retinoid homeostasis increases malformation risk in embryos exposed to pregestational diabetes. Diabetes. 2017;66:1041–51.

    Article  CAS  Google Scholar 

  52. Cogliatti SB. Diplomyelia: caudal duplication of the neural tube in mice. Teratology. 1986;34:343–52.

    Article  CAS  Google Scholar 

  53. Shum ASW, Poon LLM, Tang WWT, Koide T, Chan BWH, Leung Y-CG, Shiroishi T, Copp AJ. Retinoic acid induces down-regulation of Wnt-3a, apoptosis and diversion of tail bud cells to a neural fate in the mouse embryo. Mech Dev. 1999;84:17–30.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  55. Greene NDE, Gerrelli D, Van Straaten HWM, Copp AJ. Abnormalities of floor plate, notochord and somite differentiation in the loop-tail (Lp) mouse: a model of severe neural tube defects. Mech Dev. 1998;73:59–72.

    Article  CAS  Google Scholar 

  56. Pang D, Dias MS, Ahab-Barmada M. Split cord malformation: part I: a unified theory of embryogenesis for double spinal cord malformations. Neurosurgery. 1992;31:451–80.

    Article  CAS  Google Scholar 

  57. Bentley J, Smith JR. Developmental posterior enteric remnants and spinal malformations: the split notochord syndrome. Arch Dis Child. 1960;35:76–86.

    Article  CAS  Google Scholar 

  58. Hofmann AD, Puri P. Association of Hirschsprung’s disease and anorectal malformation: a systematic review. Pediatr Surg Int. 2013;29:913–7.

    Article  Google Scholar 

  59. Lynch SA, Wang YM, Strachan T, Burn J, Lindsay S. Autosomal dominant sacral agenesis: Currarino syndrome. J Med Genet. 2000;37:561–6.

    Article  CAS  Google Scholar 

  60. Li H, Arber S, Jessell TM, Edlund H. Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9. Nat Genet. 1999;23:67–70.

    Article  CAS  Google Scholar 

  61. Szumska D, Pieles G, Essalmani R, Bilski M, Mesnard D, Kaur K, Franklyn A, El OK, Jefferis J, Bentham J, Taylor JM, Schneider JE, Arnold SJ, Johnson P, Tymowska-Lalanne Z, Stammers D, Clarke K, Neubauer S, Morris A, Brown SD, Shaw-Smith C, Cama A, Capra V, Ragoussis J, Constam D, Seidah NG, Prat A, Bhattacharya S. VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5. Genes Dev. 2008;22:1465–77.

    Article  CAS  Google Scholar 

  62. Young T, Deschamps J. Hox, Cdx, and anteroposterior patterning in the mouse embryo. Curr Top Dev Biol. 2009;88:235–55.

    Article  CAS  Google Scholar 

  63. Tsuda T, Iwai N, Deguchi E, Kimura O, Ono S, Furukawa T, Sasaki Y, Fumino S, Kubota Y. PCSK5 and GDF11 expression in the hindgut region of mouse embryos with anorectal malformations. Eur J Pediatr Surg. 2011;21:238–41.

    Article  CAS  Google Scholar 

  64. Payne J, Shibasaki F, Mercola M. Spina bifida occulta in homozygous Patch mouse embryos. Dev Dyn. 1997;209:105–16.

    Article  CAS  Google Scholar 

  65. Aruga J, Mizugishi K, Koseki H, Imai K, Balling R, Noda T, Mikoshiba K. Zic1 regulates the patterning of vertebral arches in cooperation with Gli3. Mech Dev. 1999;89:141–50.

    Article  CAS  Google Scholar 

  66. Wallin J, Wilting J, Koseki H, Fritsch R, Christ B, Balling R. The role of Pax-1 in axial skeleton development. Development. 1994;120:1109–21.

    CAS  PubMed  Google Scholar 

  67. 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 USA. 1999;96:9695–700.

    Article  CAS  Google Scholar 

  68. Rodrigo I, Hill RE, Balling R, Münsterberg A, Imai K. Pax1 and Pax9 activate Bapx1 to induce chondrogenic differentiation in the sclerotome. Development. 2003;130:473–82.

    Article  CAS  Google Scholar 

  69. Leitges M, Neidhardt L, Haenig B, Herrmann BG, Kispert A. The paired homeobox gene Uncx4.1 specifies pedicles, transverse processes and proximal ribs of the vertebral column. Development. 2000;127:2259–67.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Ms. Lenka Filipkova for the embryo image in Fig. 21.1. The authors’ research on spinal dysraphism is supported by grants from Smiles with Grace, Great Ormond Street Hospital Children’s Charity (GOSHCC) and a Child Health Research PhD studentship. AC and NG are GOSHCC Professors.

Author information

Authors and Affiliations

  1. Newlife Birth Defects Research Unit, Institute of Child Health, University College London, London, UK

    Victoria J. Jones, Nicholas D. E. Greene & Andrew J. Copp

Authors
  1. Victoria J. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas D. E. Greene
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew J. Copp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew J. Copp .

Editor information

Editors and Affiliations

  1. Seattle Science Foundation, Seattle, WA, USA

    R. Shane Tubbs

  2. Swedish Neuroscience Institute, Seattle, WA, USA

    Rod J. Oskouian

  3. Pediatric Neurosurgery, Children’s of Alabama, Birmingham, AL, USA

    Jeffrey P. Blount

  4. Division of Neurosurgery, Children’s of Alabama, Birmingham, AL, USA

    W. Jerry Oakes

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Jones, V.J., Greene, N.D.E., Copp, A.J. (2019). Genetics and Developmental Biology of Closed Dysraphic Conditions. In: Tubbs, R., Oskouian, R., Blount, J., Oakes, W. (eds) Occult Spinal Dysraphism. Springer, Cham. https://doi.org/10.1007/978-3-030-10994-3_21

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-10994-3_21

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-10993-6

  • Online ISBN: 978-3-030-10994-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation