Neural Tube Defects


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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Further Reading

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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. [doi: 10.1002/9780470015902.a0000804.pub3]