Curly tail: a 50-year history of the mouse spina bifida model

Abstract

This paper reviews 50 years of progress towards understanding the aetiology and pathogenesis of neural tube defects (NTD) in the curly tail (ct) mutant mouse. More than 45 papers have been published on various aspects of curly tail with the result that it is now the best understood mouse model of NTD pathogenesis. The failure of closure of the spinal neural tube, which leads to spina bifida in this mouse, has been traced back to a tissue-specific defect of cell proliferation in the tail bud of the E9.5 embryo. This cell proliferation defect results in a growth imbalance in the caudal region that generates ventral curvature of the body axis. Neurulation movements are opposed, leading to delayed neuropore closure and spina bifida, or tail defects. It is interesting to reflect that these advances have been achieved in the absence of information on the nature of the ct gene product, which remains unidentified. In addition to the principal ct gene, which maps to distal Chromosome 4, the curly tail phenotype is influenced by several modifier genes and by environmental factors. NTD in curly tail are resistant to folic acid, as is thought to be the case in 30% of human NTD, whereas they can be prevented by myo-inositol. These and other features of NTD in this system bear striking similarities to the situation in humans, making curly tail a model for understanding a sub-type folic acid-resistant human NTD.

Figures

Figure 1

Adult curly tail mouse (ct/ct) with a curl in the proximal region of the tail and a healed sacral spina bifida. Such mice appear otherwise normal, are fertile, and live to old age.

Figure 2

Appearance of NTD in curly tail embryos and fetuses. (a) Curly tail embryo (E10) with 30 somites. Closure of the PNP is delayed so that it remains widely open, with everted neural folds, indicating that elevation and subsequent convergence of the neural folds are failing. This neurulation delay has been demonstrated to result from enhanced curvature of the caudal body axis, which is clearly visible in this embryo. The large size of the PNP at this stage indicates that it will not close. (b) Curly tail embryo (E11) with 40 somites. The PNP has failed to close, with the result that the neural tube is persistently open from the level of the 28th somite onwards. A marked eversion of the neural folds, and the beginning of a curled tail are visible. This non-closed PNP will develop further into spina bifida aperta. (c). Curly tail embryo (E13), exhibiting all three manifestations of the ct phenotype: exencephaly (EX), lumbosacral spina bifida (SB) and a curled tail (CT). Scale bar: 1 mm for all figures.

Figure 3

Movement of curly tail mice 1950 - 2000

Figure 4

A diagrammatic summary of our current understanding of the pathogenesis and prevention of low spinal NTD in the curly tail mouse. The central sequence depicts the molecular, cellular and tissue events that are known to occur in curly tail embryos. Left and right sides of the diagram show preventive agents and experimental interventions that can prevent curly tail NTD, with an indication of the level of the pathogenetic sequence at which these influences act.