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

van Straaten HW, Copp AJ. Curly tail: a 50-year history of the mouse spina bifida model. Anatomy and Embryolgy. 2001 Apr;203(4):225-37. Review.

Department of Anatomy and Embryology, Maastricht University, The Netherlands. h.vanstraaten@ae.unimaas.nl

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.

PMID: 11396850

Mouse models for neural tube closure defects.

Juriloff DM, Harris MJ. Mouse models for neural tube closure defects. Human Molecular Genetics. 2000 Apr 12;9(6):993-1000. Review.

Department of Medical Genetics, University of British Columbia, 6174 University Boulevard, Vancouver, British Columbia, Canada. juriloff@interchange.ubc.ca

Neural tube closure defects (NTDs), in particular anencephaly and spina bifida, are common human birth defects (1 in 1000), their genetics is complex and their risk is reduced by periconceptional maternal folic acid supplementation. There are > 60 mouse mutants and strains with NTDs, many reported within the past 2 years. Not only are NTD mutations at loci widely heterogeneous in function, but also most of the mutants demonstrate variable low penetrance and some show complex inheritance patterns (e.g. SELH/Bc, Abl / Arg, Mena / Profilin1 ). In most of these mouse models, the NTDs are exencephaly (equivalent to anencephaly) or spina bifida or both, reflecting failure of neural fold elevation in well defined, mechanistically distinct elevation zones. NTD risk is reduced in various models by different maternal nutrient supplements, including folic acid ( Pax3, Cart1, Cd mutants), inositol ( ct ) and methionine ( Axd ). Lack of de novo methylation in embryos ( Dnmt3b -null) leads to NTD risk, and we suggest a potential link between methylation and the observed female excess among cranial NTDs in several models. Some surprising NTD mutants ( Gadd45a, Terc, Trp53 ) suggest that genes with a basic mitotic function also have a function specific to neural fold elevation. The genes mutated in several mouse NTD models involve actin regulation ( Abl/Arg, Macs, Mena/Profilin1, Mlp, Shrm, Vcl ), support the postulated key role of actin in neural fold elevation, and may be a good candidate pathway to search for human NTD genes.

PMID: 10767323

Mouse models of neural tube defects: investigating preventive mechanisms.

Greene ND, Copp AJ. Mouse models of neural tube defects: investigating preventive mechanisms. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 2005 May 15;135C(1):31-41. Review.

Neural Development Unit, Institute of Child Health, University College London, UK. n.greene@ich.ucl.ac.uk

Neural tube defects (NTD), including anencephaly and spina bifida, are a group of severe congenital abnormalities in which the future brain and/or spinal cord fail to close. In mice, NTD may result from genetic mutations or knockouts, or from exposure to teratogenic agents, several of which are known risk factors in humans. Among the many mouse NTD models that have been identified to date, a number have been tested for possible primary prevention of NTD by exogenous agents, such as folic acid. In genetic NTD models such as Cart1, splotch, Cited2, and crooked tail, and NTD induced by teratogens including valproic acid and fumonisins, the incidence of defects is reduced by maternal folic acid supplementation. These folate-responsive models provide an opportunity to investigate the possible mechanisms underlying prevention of NTD by folic acid in humans. In another group of mouse models, that includes curly tail, axial defects, and the Ephrin-A5 knockout, NTD are not preventable by folic acid, reflecting the situation in humans in which a subset of NTD appear resistant to folic acid therapy. In this group of mutants alternative preventive agents, including inositol and methionine, have been shown to be effective. Overall, the data from mouse models suggests that a broad-based in utero therapy may offer scope for prevention of a greater proportion of NTD than is currently possible. Copyright 2005 Wiley-Liss, Inc

PMID: 15800852

Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: Identification of Tulp3 as a novel negative regulator of

Patterson VL, Damrau C, Paudyal A, Reeve B, Grimes DT, Stewart ME, Williams DJ, Siggers P, Greenfield A, Murdoch JN. (2009) Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: Identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway. Human Molecular Genetics. 2009 Feb 17.

Mammalian Genetics Unit.

The mammalian sonic hedgehog (Shh) signalling pathway is essential for embryonic development and the patterning of multiple organs. Disruption or activation of Shh signalling leads to multiple birth defects, including holoprosencephaly, neural tube defects and polydactyly, and in adults results in tumours of the skin or central nervous system. Genetic approaches with model organisms continue to identify novel components of the pathway, including key molecules that function as positive or negative regulators of Shh signalling. Data presented here define Tulp3 as a novel negative regulator of the Shh pathway. We have identified a new mouse mutant that is a strongly hypomorphic allele of Tulp3 and which exhibits expansion of ventral markers in the caudal spinal cord, as well as neural tube defects and preaxial polydactyly, consistent with increased Shh signalling. We demonstrate that Tulp3 acts genetically downstream of Shh and Smoothened (Smo) in neural tube patterning and exhibits a genetic interaction with Gli3 in limb development. We show that Tulp3 does not appear to alter expression or processing of Gli3, and we demonstrate that transcriptional regulation of other negative regulators (Rab23, Fkbp8, Thm1, Sufu and PKA) is not affected. We discuss the possible mechanism of action of Tulp3 in Shh-mediated signalling in light of these new data.

PMID: 19223390

Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects

Harris MJ, Juriloff DM. Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects. Birth Defects Research Part A: Clinical and Molecular Teratology. 2007 Mar;79(3):187-210. Review.

BACKGROUND: The number of mouse mutants and strains with neural tube closure defects (NTDs) now exceeds 190, including 155 involving known genes, 33 with unidentified genes, and eight "multifactorial" strains.

METHODS: The emerging patterns of mouse NTDs are considered in relation to the unknown genetics of the common human NTDs, anencephaly, and spina bifida aperta.

RESULTS: Of the 150 mouse mutants that survive past midgestation, 20% have risk of either exencephaly and spina bifida aperta or both, parallel to the majority of human NTDs, whereas 70% have only exencephaly, 5% have only spina bifida, and 5% have craniorachischisis. The primary defect in most mouse NTDs is failure of neural fold elevation. Most null mutations (>90%) produce syndromes of multiple affected structures with high penetrance in homozygotes, whereas the "multifactorial" strains and several null-mutant heterozygotes and mutants with partial gene function (hypomorphs) have low-penetrance nonsyndromic NTDs, like the majority of human NTDs. The normal functions of the mutated genes are diverse, with clusters in pathways of actin function, apoptosis, and chromatin methylation and structure. The female excess observed in human anencephaly is found in all mouse exencephaly mutants for which gender has been studied. Maternal agents, including folate, methionine, inositol, or alternative commercial diets, have specific preventative effects in eight mutants and strains.

CONCLUSIONS: If the human homologs of the mouse NTD mutants contribute to risk of common human NTDs, it seems likely to be in multifactorial combinations of hypomorphs and low-penetrance heterozygotes, as exemplified by mouse digenic mutants and the oligogenic SELH/Bc strain.

PMID: 17177317

Mini-review: toward understanding mechanisms of genetic neural tube defects in mice

Harris MJ, Juriloff DM. Mini-review: toward understanding mechanisms of genetic neural tube defects in mice. Teratology. 1999 Nov;60(5):292-305. Review.

We review the data from studies of mouse mutants that lend insight to the mechanisms that lead to neural tube defects (NTDs). Most of the 50 single-gene mutations that cause neural tube defects (NTDs) in mice also cause severe embryonic-lethal syndromes, in which exencephaly is a nonspecific feature. In a few mutants (e.g., Trp53, Macs, Mlp or Sp), other defects may be present, but affected fetuses can survive to birth. Multifactorial genetic causes, as are present in the curly tail stock (15-20% spina bifida), or the SELH/Bc strain (15-20% exencephaly), lead to nonsyndromic NTDs. The mutations indicate that "spina bifida occulta," a dorsal gap in the vertebral arches over an intact neural tube, is usually genetically and developmentally unrelated to exencephaly or "spina bifida" (aperta). Almost all exencephaly or spina bifida aperta of genetic origin is caused by failure of neural fold elevation. The developmental mechanisms in genetic NTDs are considered in terms of distinct rostro-caudal zones along the neural folds that likely differ in mechanism of elevation. Failure of elevation leads to: split face (zone A), exencephaly (zone B), rachischisis (all of zone D), or spina bifida (caudal zone D). The developmental mechanisms leading to these genetic NTDs are heterogeneous, even within one zone. At the tissue level, the mutants show that the mechanism of failure of elevation can involve, e.g., (1) slow growth of adjacent tethered tissue (curly tail), (2) defective forebrain mesenchyme (Cart1 or twist), (3) defective basal lamina in surface ectoderm (Lama5), (4) excessive breadth of floorplate and notochord (Lp), (5) abnormal neuroepithelium (Apob, Sp, Tcfap2a), (6) morphological deformation of neural folds (jmj), (7) abnormal neuroepithelial and neural crest cell gap-junction communication (Gja1), or (8) incomplete compensation for a defective step in the elevation sequence (SELH/Bc). At the biochemical level, mutants suggest involvement of: (1) faulty regulation of apoptosis (Trp53 or p300), (2) premature differentiation (Hes1), (3) disruption of actin function (Macs or Mlp), (4) abnormal telomerase complex (Terc), or (5) faulty pyrimidine synthesis (Sp). The NTD preventative effect of maternal dietary supplementation is also heterogeneous, as demonstrated by: (1) methionine (Axd), (2) folic acid or thymidine (Sp), or (3) inositol (curly tail). The heterogeneity of mechanism of mouse NTDs suggests that human NTDs, including the common nonsyndromic anencephaly or spina bifida, may also reflect a variety of genetically caused defects in developmental mechanisms normally responsible for elevation of the neural folds.

PMID: 10525207

Fetal spina bifida in a mouse model: loss of neural function in utero.

Stiefel D, Copp AJ, Meuli M. Fetal spina bifida in a mouse model: loss of neural function in utero. Journal of Neurosurgery. 2007 Mar;106(3 Suppl):213-21.

OBJECT: The devastating neurological deficit associated with myelomeningocele has previously been assumed to be a direct and inevitable consequence of the primary malformation-failure of neural tube closure. An alternative view is that secondary damage to the pathologically exposed spinal cord tissue in utero is responsible for the neurological deficiency. If the latter mechanism were shown to be correct, it would provide an objective rationale for the performance of in utero surgery for myelomeningocele, because coverage of the exposed spinal cord could be expected to alleviate or perhaps prevent neurodegeneration. To examine this question, the authors studied the development of neuronal connections and neurological function of mice during fetal and neonatal stages in a genetic model of exposed lumbosacral spina bifida.

METHODS: The persistently exposed spinal cord of mouse fetuses carrying both curly tail and loop-tail mutations exhibited essentially normal anatomical and functional hallmarks of development during early gestation (embryonic Days 13.5-16.5), including sensory and motor projections to and from the cord. A significant proportion of fetuses with spina bifida at early gestation exhibited sensorimotor function identical to that seen in age-matched healthy controls. However, at later gestational stages, increasing neurodegeneration within the spina bifida lesion was detected, which was paralleled by a progressive loss of neurological function.

CONCLUSIONS: These findings provide support for the hypothesis that neurological deficit in human myelomeningocele arises following secondary neural tissue destruction and loss of function during pregnancy.

PMID: 17465388