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

Disruption of PDGFR{alpha}-initiated PI3K activation and migration of somite derivatives leads to spina bifida

Pickett EA, Olsen GS, Tallquist MD. Disruption of PDGFR{alpha}-initiated PI3K activation and migration of somite derivatives leads to spina bifida. Development. 2008 Feb;135(3):589-98.

Spina bifida, or failure of the vertebrae to close at the midline, is a common congenital malformation in humans that is often synonymous with neural tube defects (NTDs). However, it is likely that other etiologies exist. Genetic disruption of platelet-derived growth factor receptor (PDGFR) alpha results in spina bifida, but the underlying mechanism has not been identified. To elucidate the cause of this birth defect in PDGFRalpha mutant embryos, we examined the developmental processes involved in vertebrae formation. Exposure of chick embryos to the PDGFR inhibitor imatinib mesylate resulted in spina bifida in the absence of NTDs. We next examined embryos with a tissue-specific deletion of the receptor. We found that loss of the receptor from chondrocytes did not recapitulate the spina bifida phenotype. By contrast, loss of the receptor from all sclerotome and dermatome derivatives or disruption of PDGFRalpha-driven phosphatidyl-inositol 3' kinase (PI3K) activity resulted in spina bifida. Furthermore, we identified a migration defect in the sclerotome as the cause of the abnormal vertebral development. We found that primary cells from these mice exhibited defects in PAK1 activation and paxillin localization. Taken together, these results indicate that PDGFRalpha downstream effectors, especially PI3K, are essential for cell migration of a somite-derived dorsal mesenchyme and disruption of receptor signaling in these cells leads to spina bifida.

PMID: 18192285