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

Abstract

SummaryThis 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, but can be prevented by myoinositol. 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 of human NTD.

Early mesodermal phenotypes in splotch suggest a role for Pax3 in the formation of epithelial somites

“…In the area of the open neural tube, the dorsal part of the neural arches was missing. However, as in human patients with spina bifida (Larsen, 1993), or in the spina bifida-affected mouse mutant curly tail (reviewed by Grü neberg, 1963;Töndury and Theiler, 1990;van Straaten and Copp, 2001), all other elements of the vertebral column were clearly separated and presented a normal morphology. This finding suggests that the fused and malformed vertebrae in Sp d homozygotes and compound heterozygotes result directly from the impaired Pax3 function in the paraxial mesoderm rather than indirectly from the compromised neural tube.…”

“…However, these vertebral malformations, although less pronounced, were also present at axial levels not affected by rachischisis. Moreover, in human patients and mice suffering from rachischisis, for instance the mouse mutant curly tail, although the neural arches fail to close and spinous processes are absent, the remaining vertebral components remain unchanged (reviewed by Grü neberg, 1963;Töndury and Theiler, 1990;Larsen, 1993;van Straaten and Copp, 2001; see also Mouse Locus Catalogue, Jackson Laboratory). Therefore, the irregular and fused vertebral bodies, neural arches, and ribs seen in the allelic series of Splotch mutants constitute a generalised vertebral column phenotype that randomly affects all axial levels.…”

Neural tube defects and folate: case far from closed

“…Although variable low penetrance is found in some mutant models, only a few strains, including SELH/Bc and curly tail strains, show the complex inheritance patterns and responsiveness to nutritional supplementation that are indicative of human non-syndromic NTDs 74,75 . To our knowledge, the discovery of genes that cause NTDs when disrupted in mouse models has not as yet led to the identification of a genetic basis for human non-syndromic NTDs.…”

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

“…28 The curly tail (ct) mutation is a hypomorphic allele of the Grhl3 (grainyhead-like 3) gene that arose spontaneously on the GFF inbred mouse strain background. 29 Homozygous mutants develop neural tube defects (NTDs), but variability in the proportion of affected individuals across strain backgrounds suggests that genetic variants modify penetrance. De Castro and colleagues used proteomic analysis to identify a variant of Lmnb1 (lamin B1) that reduces occurrence of spina bifida in this model.…”