06-P026 Morphological and morphometric analyses of rats fetuses exposed to antiepileptic drugs

Neural tube defects (NTDs), such as spina bifida and anencephaly, are severe birth defects which result from failure of closure of the neural tube (the precursor of the brain and the spinal cord). In humans, NTDs affect 1 per 1000 pregnancies, with multifactorial aetiology suggestive of a combination of one or more genetic factors with contribution from environmental risk factors. The curly tail (ct/ct) mouse represents an established model for NTDs; affected embryos develop spina bifida which closely resembles the corresponding birth defects in humans both in terms of pathology and multifactorial etiology. The major genetic defect in curly tail is a regulatory mutation that results in reduced expression of grainyhead-like-3 (Grhl3). We identified a putative regulatory mutation in the Grhl3 gene, and showed by transgenic BAC rescue that increased expression of Grhl3 prevents NTDs in ct/ct embryos. However, the penetrance is strongly influenced by, as yet unidentified modifier genes. In the course of proteomic analysis of curly tail we identified differences in the migration of lamin B1 on 2D gels, between samples from ct/ct embryos and a closely matched wild-type strain. Migration differences have been found to result from a genomic polymorphism that results in variation in protein sequence. Analysis of sub-strains of mice carrying different combinations of the laminB1 polymorphism and the Grhl3 mutation suggest that Lmnb1 could potentially act as a modifier of NTD risk in curly tail mice.