Towards the long term aim of understanding vertebrate development at the molecular level, the immediate objective of this work is to understand the function and activities of a newly identified gene. The noggin gene was identified in a functional screen for molecules which induce a dorsal-ventral axis in the amphibian Xenopus. The gene is expressed in parts of the embryo which have dorsal organizing activity, including the Spemann organizer. The gene encodes a novel secreted polypeptide whose function will be investigated at several levels. First we will express and purify the protein; purified protein will be used to study the properties of the polypeptide and will be used as a ligand to isolate the receptor for noggin. The properties of the receptor and the second messenger pathway that it activates in the target cell will be studied. In the second part of the project the role of the noggin gene in normal development of vertebrates will be determined. Dominant negative mutations in the noggin ligand or receptor will be made and tested. the mutant will be reintroduced into embryos as messenger RNA to study the consequences of disrupting noggin function. To test the generality of importance of the noggin gene a mouse noggin homolog, which shares extensive sequence identity with the frog gene, will be used to test the similarity of expression, and will be used to disrupt the mouse gene in order to study the developmental consequences of a null allele. In the third part of the project the biological activities of noggin protein will be tested. Is noggin responsible for the activities of the Spemann organizer, including neural induction? The possibility that noggin has effects on growth or differentiation of cells in the differentiated animal is suggested by the late pattern of expression in skeletal, neural and mesenchymal tissues. Other growth factors that are active in early development (fibroblast growth factor and activin) have distinct roles in later growth and differentiation. The biological effects of noggin on specific target tissues will be tested with a particular view towards identifying any useful therapeutic possibilities in human disease. These may include use as a growth factor for tissue culture, use as a growth or differentiation factor in wound healing, or use as a trophic factor in degenerative diseases.