Our laboratory has been interested in several aspects of signal transduction resulting from binding of polypeptide hormones to their surface receptors on cells. One major topic under study is the role of direct substrates for protein kinase C (PKC) in mediating the many cellular effects resulting from activation of this family of kinases by hormones and other agonists. We have been studying a small family of PKC substrates consisting of MARCKS and its smaller homologue, the MARCKS-like protein or MLP. Ongoing projects include structure-function studies of the protein and its mutant derivatives in two major systems, development of the mouse central nervous system, and early embryogenesis in Xenopus laevis. These studies include creating double knockouts for MARCKS and MLP in the mouse, and using knockout oligonucleotides in early Xenopus development. In addition, transgenic complementation of the knockout mice with various mutant proteins are continuing in order to analyze structure function relationships in development. Similar studies are being performed in a cell transfection system, which seeks to examine the effect of the wild-type and mutant proteins on cellular adhesiona and migration on various matrices. A novel two-hybrid screen is also being conducted in an attempt to identify MARCKS and MLP associated proteins other than PKC. Finally, we are investigating the possibility that mutations in the MARCKS and MLP genes are involved in human neural tube defects, particularly at the level of increasing a genetic predisposition to environmental causes of these defects. - anencephaly; exencephaly; neuronal leptomeningeal ectopia; retinal development; Xenopus; corpus callosum
