The aim of this proposal is to investigate the role of the transforming growth factor beta-related protein, DVR-6 (also known as Vgr-1 and Bone Morphogenetic Protein, BMP-6), in the growth and differentiation of the mouse embryo. Previous studies have shown that the DVR-6 gene is expressed in a variety of developing tissues, including the supranasal cells of the epidermis, the central and peripheral nervous system, cartilage, ovary, and pre-and postnatal kidney and lung. Based on known functions for other members of the TGFbeta superfamily, both in vertebrates and invertebrates, our hypothesis is that DVR-6 secreted by one cell type binds to receptors on a neighboring cell type and elicits changes in gene expression, proliferation and cell fate. A variety of approaches will be used to test this hypothesis for DVR-6 in the mouse. (1) DVR-6 protein will be misexpressed in transgenic mice, using heterologous gene regulatory regions. Initially, the bovine cytokeratin III gene promoter will be used to misexpress DVR-6 in the basal cells of the developing epidermis, and the mouse En-2 promoter will be used to misexpress the protein in the mid/hind brain region of the CNS. (2) Affinity purified antibodies against the C-terminal region of DVR-6 will be generated and used to study the biosynthesis, post-transnational modification, and extracellular location of the mature protein in vitro and in vivo. (3) DVR-6 will be purified from the conditioned medium of CHO cells and used to study the effect of the protein on a variety of neuronal cells in culture. In the long term the results will contribute to our understanding of the complex mechanisms regulating the growth, differentiation and morphogenesis of both embryonic tissue and adult tissues undergoing regeneration and repair. Disruption of these processes can lead to congenital malformations and cancers.
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