Neural Tube Defects

Abstract

Neural tube defects are malformations of the central nervous system and axial skeleton that arise before birth, and range from the fatal to the asymptomatic. They are among the commonest birth defects and can affect the brain, as in anencephaly, or the low spine, as in spina bifida. The defects have a strong genetic element, with a role for ‘planar polarity’ genes that control the elongation of the early embryo and cellular enzymes that metabolise folates. Environmental risk factors include maternal diabetes and antiepileptic drugs. Studies of mouse embryos reveal how the neural tube closes normally, and what can go wrong leading to a defect. The actin cytoskeleton is crucial, as is the balance between proliferation and differentiation of neural cells. Folic acid can reduce the risk of a neural tube defect, when taken in early pregnancy, although it does not prevent all cases. Other supplements, including inositol, are under investigation to see whether the prevention offered by folic acid can be enhanced in future.

Key Concepts

  • Neural tube defects are common, disabling birth defects of the central nervous system.
  • Several types of neural tube defects occur, depending on the embryonic event that goes wrong.
  • Neural tube closure is the key developmental event whose disturbance leads to spina bifida and anencephaly.
  • Genes and environmental factors interact to cause neural tube defects.
  • Genes of folate one‐carbon metabolism, and of the planar cell polarity pathway, are known to participate in the causation of neural tube defects.
  • Many cellular events of embryonic development have been implicated in the development of neural tube defects.
  • Folic acid supplements in early pregnancy can prevent some cases of neural tube defect.
  • Novel therapies are required for the primary prevention of neural tube defects that do not respond to folic acid.

Keywords: birth defects; nervous system; embryo; genes; developmental biology

Figure 1. Multisite closure of the neural tube in the mouse embryo. Schematic summary of the successive initiation events of mouse neurulation (Closures 1, 2 and 3), the direction of spread of closure from the initiation sites (solid arrows) and the sites of completion of closure (anterior, hindbrain and posterior neuropores). The tail bud region (red shading) is the site of secondary neurulation which follows immediately after closure of the posterior neuropore. The main types of neural tube defect that result from failure of the different components of neurulation are indicated by the dotted arrows. Modified with permission from Copp and Bernfield (1994) © Wolters Kluwer Health Inc.
Figure 2. An embryological classification of neural tube defects.
Figure 3. The spectrum of human and mouse neural tube defects. (a) Myelomeningocele in a human neonate; (b) Myelocele extending from thoracic to sacral levels in a neonate; (c, d) Craniorachischisis in a human foetus from side (c) and back view (d). Most of the brain and spine are open; (e) Hydrocephalus, with marked expansion of the cranial vault; (f) Occipital encephalocele in which a large portion of the brain, contained within a meningeal sac, has herniated through a defect in the posterior part of the skull; (g) Hairy skin lesion overlying an asymptomatic spina bifida occulta, which could only be detected by abdominal radiography; (h) Exencephaly (arrow) and open spina bifida (arrowhead) in an E15.5 mouse embryo homozygous for the curly tail mutation; (i) Open spina bifida in an E18.5 curly tail; Vangl2 double mutant mouse foetus. Note the close similarity between this mouse defect and human myelocele in (b); (j) Craniorachischisis in an E15.5 mouse foetus homozygous for a mutation of Celsr1. The neural tube is open between the arrows, affecting most of the brain and the entire spine. (a, c–e) Modified from Copp (2005) © Wiley‐VCH, Weinheim. (h, j) Modified from Copp et al. (2003) © Nature Publishing Group. (i) Modified from Stiefel et al. (2003) © The authors.
Figure 4. The principal biochemical reactions of folate one‐carbon metabolism (FOCM). The main reaction intermediates (black text) move one‐carbon units around the pathways, generating the main FOCM outputs (pink text): synthesis of purines and pyrimidines (nucleotides) for DNA synthesis and donation of methyl groups to DNA, RNA and other macromolecules. MTHFR (blue text) is a key enzyme regulating the production of 5‐methyl‐THF, essential for the conversion of homocysteine to methionine. Mitochondrial FOCM (purple box) is a major contributor of one‐carbon units via export of formate ions. Note that dietary folate and folic acid (green text) enter FOCM at different points. Abbreviations: DHF, dihydrofolate; SAH, s‐adenosyl homocysteine; SAM, s‐adenosyl methionine; THF, tetrahydrofolate; TMP, thymidine monophosphate.
Figure 5. Normal and abnormal initiation of neurulation (Closure 1) in the mouse embryo. Scanning electron microscopy of: (a) Whole E8.5 embryo demonstrating the approaching neural folds approximately half way along the body axis, indicating the incipient Closure 1 event. This event occurs at the boundary of the hindbrain and cervical regions. (b, c) Sections transverse to the body axis as indicated by the red line in (a). A wild‐type embryo (b) shows bending at a compact midline hinge point, and straight lateral neural folds. A homozygous loop‐tail (Vangl2) mutant embryo (c) shows disturbance of the midline which is broader than normal, without a compact bend in the neural plate. Although the neural folds elevate normally, they are not able to appose and fuse in the midline, leading to craniorachischisis in mutant embryos. Abbreviations: am, amnion; hnf, hindbrain neural folds; tnf, thoracic neural folds; ys, yolk sac. Modified from (a) Copp et al., 1990, © Elsevier. (b, c) Greene et al. (1998) © Elsevier.
Figure 6. Molecular regulation of dorsolateral bending in mouse neural tube closure. The morphology of neural tube closure changes from (a) high spinal to (b) low spinal regions of the mouse embryo. In the upper spine, the neural plate bends only in the midline, at the median hinge point (MHP), whereas in the low spine, bending occurs at dorsolateral hinge points (DLHPs). (c) Summary of the molecular interactions regulating DLHP formation. In the upper spine, DLHPs are absent because of unopposed inhibition by BMP2. Although transcription of Noggin is stimulated by BMP2 at all levels of the body axis, Shh expression from the notochord is strong in the upper spine, inhibiting Noggin expression. In the lower spine, Shh influence is reduced, Noggin expression is deinhibited and the inhibitory influence of BMP2 antagonised, allowing DLHPs to form. Yellow triangles: MHP; red triangles: DLHPs; green arrows: stimulatory interactions; red lines: inhibitory interactions; dashed lines: inactive influences. (c) Modified from Ybot‐Gonzalez et al. (2007a) © Palgrave MacMillan.
Figure 7. Cellular and morphogenetic processes required for neural tube closure. The cranial neural folds are depicted in the midbrain of the mouse embryo. Elevation is initially through neural fold expansion to create a biconvex morphology (a). Subsequently, dorsolateral bending occurs (b), causing the tips of the neural folds to converge on the midline, ensuring fusion and completion of cranial neurulation. Mesodermal expansion appears the most important morphogenetic factor in the initial elevation of the neural folds (a). At later stages, cranial neurulation requires additional processes including a functional actin cytoskeleton, successful initiation of neural crest emigration, precisely regulated programmed cell death and continuation of regulated neuroepithelial cell proliferation, with postponement of neuronal differentiation until after closure is complete (b). Defects in each of these processes is seen in one or more of the gene knockout mice with neural tube defects. In each case, cranial neural tube closure fails and embryos develop exencephaly.
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References

Adzick NS, Sutton LN, Crombleholme TM, et al. (1998) Successful fetal surgery for spina bifida. Lancet 352: 1675–1676.

Adzick NS, Thom EA, Spong CY, et al. (2011) A randomized trial of prenatal versus postnatal repair of myelomeningocele. New England Journal of Medicine 364: 993–1004.

Amorim MR, Lima MA, Castilla EE, et al. (2007) Non‐Latin European descent could be a requirement for association of NTDs and MTHFR variant 677C > T: a meta‐analysis. American Journal of Medical Genetics Part A 143A: 1726–1732.

Blom HJ, Shaw GM, Den Heijer M, et al. (2006) Neural tube defects and folate: case far from closed. Nature Reviews Neuroscience 7: 724–731.

Copp AJ, Brook FA, Estibeiro JP, Shum AS and Cockroft DL (1990) The embryonic development of mammalian neural tube defects. Progress in Neurobiology 35 (5): 363–403.

Copp AJ and Bernfield M (1994) Etiology and pathogenesis of human neural tube defects: insights from mouse models. Current Opinion in Pediatrics 6: 624–631.

Copp AJ, Greene ND and Murdoch JN (2003) The genetic basis of mammalian neurulation. Nature Reviews Genetics 4: 784–793.

Copp AJ (2005) In: Meyers RA (ed) Encyclopedia of Molecular Cell Biology and Molecular Medicine, vol. 9, pp. 119–138. Wiley‐VCH: Weinheim.

Copp AJ and Greene NDE (2010) Genetics and development of neural tube defects. Journal of Pathology 220: 217–230.

Eichholzer M, Tonz O and Zimmermann R (2006) Folic acid: a public‐health challenge. Lancet 367: 1352–1361.

Gelineau‐van Waes J, Rainey MA, Maddox JR, et al. (2012) Increased sphingoid base‐1‐phosphates and failure of neural tube closure after exposure to fumonisin or FTY720. Birth Defects Research, Part A: Clinical and Molecular Teratology 94: 790–803.

Greene ND, Gerrelli D, Van Straaten HW and Copp AJ (1998) Abnormalities of floor plate, notochord and somite differentiation in the loop‐tail (Lp) mouse: a model of severe neural tube defects. Mechanisms of Development 73 (1): 59–72.

Greene ND and Copp AJ (2014) Neural tube defects. Annual Review of Neuroscience 37: 221–242.

Harris MJ and Juriloff DM (2010) 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 Research, Part A: Clinical and Molecular Teratology 88: 653–669.

Hashimoto H, Robin FB, Sherrard KM, et al. (2015) Sequential contraction and exchange of apical junctions drives zippering and neural tube closure in a simple chordate. Developmental Cell 32: 241–255.

Hildebrand JD and Soriano P (1999) Shroom, a PDZ domain‐containing actin‐binding protein, is required for neural tube morphogenesis in mice. Cell 99: 485–497.

Juriloff DM and Harris MJ (2012) A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects. Birth Defects Research, Part A: Clinical and Molecular Teratology 94: 824–840.

Keller R, Shook D and Skoglund P (2008) The forces that shape embryos: physical aspects of convergent extension by cell intercalation. Physical Biology 5: 15007.

Kim TH, Goodman J, Anderson KV, et al. (2007) Phactr4 regulates neural tube and optic fissure closure by controlling PP1‐, Rb‐, and E2F1‐regulated cell‐cycle progression. Developmental Cell 13: 87–102.

Lammer EJ, Sever LE and Oakley GP (1987) Teratogen update: valproic acid. Teratology 35: 465–473.

Leck I (1974) Causation of neural tube defects: clues from epidemiology. British Medical Bulletin 30: 158–163.

MacDonald KB, Juriloff DM and Harris MJ (1989) Developmental study of neural tube closure in a mouse stock with a high incidence of exencephaly. Teratology 39: 195–213.

Massa V, Savery D, Ybot‐Gonzalez P, et al. (2009) Apoptosis is not required for mammalian neural tube closure. Proceedings of the National Academy of Sciences of the United States of America 106: 8233–8238.

Missmer SA, Suarez L, Felkner M, et al. (2006) Exposure to fumonisins and the occurrence of neural tube defects along the Texas‐Mexico border. Environmental Health Perspectives 114: 237–241.

Momb J, Lewandowski JP, Bryant JD, et al. (2013) Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice. Proceedings of the National Academy of Sciences of the United States of America 110: 549–554.

Morriss‐Kay GM and Wilkie AOM (2005) Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies. Journal of Anatomy 207: 637–653.

MRC Vitamin Study Research Group (1991) Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet 338: 131–137.

Murdoch JN, Damrau C, Paudyal A, et al. (2014) Genetic interactions between planar cell polarity genes cause diverse neural tube defects in mice. Disease Models and Mechanisms 7: 1153–1163.

Narisawa A, Komatsuzaki S, Kikuchi A, et al. (2012) Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans. Human Molecular Genetics 21: 1496–1503.

Nishimura T, Honda H and Takeichi M (2012) Planar cell polarity links axes of spatial dynamics in neural‐tube closure. Cell 149: 1084–1097.

Nonomura K, Yamaguchi Y, Hamachi M, et al. (2013) Local apoptosis modulates early mammalian brain development through the elimination of morphogen‐producing cells. Developmental Cell 27: 621–634.

O'Rahilly R and Müller F (2002) The two sites of fusion of the neural folds and the two neuropores in the human embryo. Teratology 65: 162–170.

Pai YJ, Leung KY, Savery D, et al. (2015) Glycine decarboxylase deficiency causes neural tube defects and features of non‐ketotic hyperglycinemia in mice. Nature Communications 6: 6388.

Parle‐McDermott A, Pangilinan F, O'Brien KK, et al. (2009) A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency. Human Mutation 30: 1650–1656.

Rampersaud E, Melvin EC and Speer MC (2006) Nonsyndromic neural tube defects: genetic basis and genetic investigations. In: Wyszynski DF (ed) Neural Tube Defects: From Origin to Treatment, pp. 165–175. Oxford: Oxford University Press.

Saadai P, Wang A, Nout YS, et al. (2013) Human induced pluripotent stem cell‐derived neural crest stem cells integrate into the injured spinal cord in the fetal lamb model of myelomeningocele. Journal of Pediatric Surgery 48: 158–163.

Shindo A and Wallingford JB (2014) PCP and septins compartmentalize cortical actomyosin to direct collective cell movement. Science 343: 649–652.

Smithells RW, Sheppard S, Schorah CJ, et al. (1981) Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Archives of Disease in Childhood 56: 911–918.

Stiefel D, Shibata T, Meuli M, et al. (2003) Tethering of the spinal cord in mouse fetuses and neonates with spina bifida. J. Neurosurg. (Spine) 99: 206–213.

Stiefel D, Copp AJ and Meuli M (2007) Fetal spina bifida: loss of neural function in utero. Journal of Neurosurgery 106: 213–221.

Suzuki M, Morita H and Ueno N (2012) Molecular mechanisms of cell shape changes that contribute to vertebrate neural tube closure. Development, Growth and Differentiation 54: 266–276.

Szymanska K, Hartill VL and Johnson CA (2014) Unraveling the genetics of Joubert and Meckel‐Gruber syndromes. Journal of Pediatric Genetics 3: 65–78.

Tibbetts AS and Appling DR (2010) Compartmentalization of mammalian folate‐mediated one‐carbon metabolism. Annual Review of Nutrition 30: 57–81.

Tzouanacou E, Wegener A, Wymeersch FJ, et al. (2009) Redefining the progression of lineage segregations during mammalian embryogenesis by clonal analysis. Developmental Cell 17: 365–376.

Van Allen MI, Kalousek DK, Chernoff GF, et al. (1993) Evidence for multi‐site closure of the neural tube in humans. American Journal of Medical Genetics 47: 723–743.

Wallingford JB and Harland RM (2002) Neural tube closure requires Dishevelled‐dependent convergent extension of the midline. Development 129: 5815–5825.

Waters AM and Beales PL (2011) Ciliopathies: an expanding disease spectrum. Pediatric Nephrology 26: 1039–1056.

Wilson V, Olivera‐Martinez I and Storey KG (2009) Stem cells, signals and vertebrate body axis extension. Development 136: 1591–1604.

Ybot‐Gonzalez P and Copp AJ (1999) Bending of the neural plate during mouse spinal neurulation is independent of actin microfilaments. Developmental Dynamics 215: 273–283.

Ybot‐Gonzalez P, Gaston‐Massuet C, Girdler G, et al. (2007a) Neural plate morphogenesis during mouse neurulation is regulated by antagonism of BMP signalling. Development 134: 3203–3211.

Ybot‐Gonzalez P, Savery D, Gerrelli D, et al. (2007b) Convergent extension, planar‐cell‐polarity signalling and initiation of mouse neural tube closure. Development 134: 789–799.

Further Reading

Colas JF and Schoenwolf GC (2001) Towards a cellular and molecular understanding of neurulation. Developmental Dynamics 221: 117–145.

Copp AJ (2005) Neurulation in the cranial region – normal and abnormal. Journal of Anatomy 207: 623–635.

Copp AJ, Stanier P and Greene ND (2013) Neural tube defects: recent advances, unsolved questions, and controversies. Lancet Neurology 12: 799–810.

Copp AJ, Adzick NS, Chitty LS, et al. (2015) Spina bifida. Nature Reviews Disease Primers 1: 20157.

Harding BN and Copp AJ (2008) Malformations. In: Love S, Louis DN and Ellison DW (eds) Greenfield's Neuropathology, vol. 8, pp. 335–479. London: Hodder Arnold.

Obladen M (2011) Cats, frogs, and snakes: early concepts of neural tube defects. Journal of Child Neurology 26: 1452–1461.

Wallingford JB, Niswander LA, Shaw GM, et al. (2013) The continuing challenge of understanding, preventing, and treating neural tube defects. Science 339: 1222002.

Wilde JJ, Petersen JR and Niswander L (2014) Genetic, epigenetic, and environmental contributions to neural tube closure. Annual Reviews of Genetics 48: 583–611.

Zohn IE (2012) Mouse as a model for multifactorial inheritance of neural tube defects. Birth Defects Research. Part C, Embryo Today 96: 193–205.

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How to Cite close
Copp, Andrew J, and Greene, Nicholas DE(Jan 2016) Neural Tube Defects. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000804.pub3]