Dysmorphogenic effects of a specific protein kinase C inhibitor during neurulation

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 1998-09, Vol.12 (5), p.525-534
• Main Authors: Ward, Keith W, Rogers, Ellen H, Hunter, E.Sidney
• Format: Article
• Language: English
• Subjects: Alkaloids - pharmacology; Animals; Biological and medical sciences; Carbazoles; Chemical and industrial products toxicology. Toxic occupational diseases; Culture Techniques; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; embryo culture; Embryology: invertebrates and vertebrates. Teratology; Embryonic and Fetal Development - drug effects; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Gastrula - drug effects; Indoles - pharmacology; Maleimides - pharmacology; MAPK; Medical sciences; Mice; Mice, Inbred Strains; Mitogen-Activated Protein Kinase Kinases; Morphogenesis - drug effects; Nervous System - drug effects; Nervous System - embryology; neurulation; PKA; PKC; PKG; Protein Kinase C - antagonists & inhibitors; Protein Kinase Inhibitors; Pyrroles - pharmacology; signal transduction; Teratology. Teratogens; Toxicology; Various organic compounds
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/S0890-6238(98)00032-X

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 μ M. 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.