A deletion encompassing Zic3 in Bent tail, a mouse model for X-linked neural tube defects

Bent tail is a mouse model for human neural tube defects. Bent tail mice ar e characterized by a shortened, kinked tail, We have observed numerous aber rations in Bent tail embryos including exencephaly, rotation defects and oc casionally omphalocele, orofacial schisis and situs abnormalities. Exenceph aly was seen in >10% of all embryos and resulted from a closure defect of t he hindbrain, Bent fail maps to the proximal part of the X chromosome. By h aplotype analysis we have appointed the Bent tail locus to a 1.1 cM interva l between markers DXMit159 and DXMit143, Subsequent analysis has revealed t he presence of a deletion in all affected animals. The deletion is similar to 1 Mb in size and encompasses the gene for Zic3, a zinc finger transcript ion factor expressed in murine neuroectoderm and dorsal axial mesoderm duri ng neurulation, Zic3 is a homolog of the Drosophila segmentation gene odd-p aired. Although the Bent tail phenotype probably is the result of the delet ion of several genes, combining data on Zic3 expression and function of Zic genes in the mouse shows that deletion of Zic3 alone is compatible with a major role of this gene in the congenital malformations of the Bent tail mo use. In man, mutations in ZIC3 are associated with situs abnormalities. The se patients occasionally also show spina bifida, indicating that genetic va riation in human ZIC3 may contribute to other congenital malformations, inc luding neural tube defects.