Neural crest cell motility in valproic acid.
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 0.75-3.0mM 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 3mM decreased cellular spreading. Area and perimeter change per minute were reduced, but migration velocity was not. VPA at 2mM reduced proliferation 11% and 3mM 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.
Fuller
Leah C
LC
Department of Biology, University of Northern Iowa, Cedar Falls, IA 50614, USA.
Cornelius
Shannon K
SK
Murphy
Charles W
CW
Wiens
Darrell J
DJ
D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002642:Chick Embryo; D003599:Cytoskeleton / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004338:Drug Combinations; D005492:Folic Acid / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D007365:Intercellular Junctions / Q000187:drug effects; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D009432:Neural Crest / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D014635:Valproic Acid / Q000633:toxicity*
D000927:Anticonvulsants; D004338:Drug Combinations; D014635:Valproic Acid; D005492:Folic Acid; D001973:Bromodeoxyuridine