This is a renewal application to continue work using gene targeting and other modern molecular and genetic methods to study the developmental regulation of early mammalian development. Emphasis will be placed on the 413.d insertional mutation and on the role of several bone morphogenetic proteins (BMP), BMP-5, BMP-6 and BMP-7. 413.d appears to control mesoderm formation in part because expression is restricted to cells surrounding the anterior tip of the primitive streak (i.e., Hensen's node, blastopore lip) and because mutant mice fail to form mesoderm. BMP proteins are an important sub-family in the TGF-beta family of genes. This large family has overlapping expression patterns and presumably overlapping functions. They are thought to be involved in inductive processes and some are involved in dorso-ventral patterning. By using a combination of knock-out mutations, molecular markers for cells and proteins, complementation with spontaneous mutations, reporter gene constructs, and other strategies, the applicant proposes comprehensive studies of the function of genes that regulate early stages of embryonic development.
