Neural crest cell motility in valproic acid

Abstract

Neural crest cells (NCCs) exit the dorsal neural tube and migrate to sites where they form diverse tissues. Valproic acid (VPA) is an anticonvulsant drug that induces neural tube and related defects. Altered NCC migration and proliferation have been proposed as mechanisms of teratogenicity. We cultured neural tube segments from chick embryos in 0.75–3.0 mM VPA. We used image analysis, proliferation assays, and fluorescence localization to investigate NCCs during VPA exposure. VPA inhibited attachment of explants and the number that produced migrating cells. VPA markedly decreased the proportion of cells migrating individually, promoting migration as epithelial sheets. VPA at 3 mM decreased cellular spreading. Area and perimeter change per minute were reduced, but migration velocity was not. VPA at 2 mM reduced proliferation 11% and 3 mM arrested proliferation. Immunostaining of VPA-exposed explants revealed N-cadherin-positive cell boundaries within sheets, but independent NCCs did not stain. F-actin staining was reduced in independent NCCs. The data support a VPA mechanism involving interference with epithelial–mesenchymal transition.