Dysmorphogenic effects of a specific protein kinase C inhibitor during neurulation.
Protein kinase C (PKC) plays a key role in signal transduction and is an important mediator of events throughout development. However, no information exists regarding the effect of a specific PKC inhibitor on mammalian embryogenesis during neurulation. This investigation was undertaken to examine the effects of a specific inhibitor of PKC, as well as inhibitors of other important kinases, on cultured mouse embryos. CD-1 mouse embryos (3 to 6 somite stage) were exposed to bisindolylmaleimide I (a specific PKC inhibitor) as well as specific inhibitors of PKA, PKG, and MAP kinase kinase for 24 h. The PKC inhibitor was a potent embryotoxicant and elicited malformations at concentrations as low as 0.01 microM. Inhibitors of other kinases also produced malformations but at much higher concentrations than those required to produce similar defects with the PKC inhibitor. These data suggest that PKC plays an important role in mammalian neurulation. Further research is required to clarify the mechanism by which PKC inhibition at this developmental stage produces malformations and the potential effects of environmental toxicants with PKC inhibitory properties on this signal transduction pathway.
Ward
K W
KW
Curriculum in Toxicology, University of North Carolina at Chapel Hill, USA.
Rogers
E H
EH
Hunter
E S
ES
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002227:Carbazoles; D046508:Culture Techniques; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D005314:Embryonic and Fetal Development / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D005775:Gastrula / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D020929:Mitogen-Activated Protein Kinase Kinases; D009024:Morphogenesis / Q000187:drug effects*; D009420:Nervous System / Q000187:drug effects* / Q000196:embryology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors; D011758:Pyrroles / Q000494:pharmacology
D000470:Alkaloids; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C115989:bisindolylmaleimide V; C073601:KT 5823; C057416:KT 5720; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases; C070515:bisindolylmaleimide I; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one