Neural Tube Closure - Normal and Abnormal

Author: Andrew Copp
Submitted: Monday 14th of September 2009 02:14:48 PM
Submitted by: egf
Educational levels: qc2, qc3


Neurulation is a key event in central nervous system development, in which bending and subsequent fusion of the edges of the neural plate culminates in the formation of the neural tube, the precursor of the brain and spinal cord [1]. Failure of neural tube closure results in neural tube defects (NTDs) in which the lumen of the neural tube remains open to the amniotic fluid environment. Degeneration of the neuroepithelium occurs later in gestation leading to neurological deficit by the time of birth, and severe handicap from the newborn period onwards [2]. While a strong genetic predisposition to human NTDs is generally accepted, the genes that mediate this predisposition have been difficult to identify. In contrast, over 100 genes are known to be required for mouse neural tube closure, by virtue of the NTD phenotypes when they are inactivated in knockout or mutant strains. In this talk, three types of genetic mouse NTDs will be described. (1) Failure of the initial step of neurulation leads to the most severe NTD, craniorachischisis, in which the neural tube remains open from midbrain to low spine. Recent studies show that initiation of neurulation requires signalling via the non-canonical Wnt/dishevelled (planar cell polarity) pathway, which regulates the cell movements of convergent extension [3]. (2) Disruption of dorso-lateral neural plate bending in the low spinal region prevents the neural fold tips from coming into apposition, leading to lumbo-sacral spina bifida. Our studies demonstrate an essential role for signalling via the BMP and Sonic hedgehog pathways in regulating neural plate bending [4]. (3) Re-opening of the closed neural tube can yield a variety of NTDs, including isolated thoracic spina bifida, not previously seen in mouse genetic models. Studies in a new genetic knockout strain demonstrate that NTDs can result from re-opening as well as failure of neural tube closure. Primary prevention of NTDs is now practised clinically using peri-conceptional folic acid therapy. In order to understand the mechanisms of action of folic acid, it is useful to identify mouse models of folate-preventable NTDs. Here, the splotch (Pax3) mouse will be described in which recent studies demonstrate a strong interaction between genetic predisposition and folate status. Since a proportion of NTDs in humans and mice do not respond to folic acid, an alternative therapy is required. We have described the use of inositol as an alternative, adjunct therapy where folic acid is ineffective, in the curly tail (Grhl3) mutant mouse [5, 6]. Studies of the action of inositol in preventing NTDs in mice will be described, as well as a new clinical trial to evaluate inositol as a preventive agent for NTDs in human pregnancy.


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Andrew Copp. Neural Tube Closure - Normal and Abnormal. EUROGENE portal. September 2009. online:

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