Regulation of Xenopus Embryonic Development by TGFbeta Superfamily Ligands and SM

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DESCRIPTION (provided by applicant): Our long term goal is to understand how members of the TGF¿ superfamily act to exert a wide range of cell- type specific actions during development. Our current focus is on the role of TGF¿ ligands and their primary signal transducers, the Smads, in two sets of developmental events: 1) the regulation of migration of cell populations that establish the craniofacial skeleton and the body wall musculature; 2) the normal growth of the tail and the regeneration of this structure following surgical extirpation. Migration of cell populations over extended distances in the embryo prior to their terminal differentiation is a critical component of the establishment of embryonic pattern. These migrations involve cell behaviors and regulatory programs which may be recapitulated during tumor metastasis, making an understanding of their regulation important for tumor biology as well as embryology. The craniofacial skeleton is made up primarily of neural crest cells that migrate from the edge of the anterior neural plate into the craniofacial region, where they differentiate into cartilage and bone. The muscle of the body wall is made up of muscle precursor cells that migrate from the somites to the ventro-lateral body wall, where they differentiate into muscle. In each case, preliminary work implicates BMP signals as regulators of the cell migration and/or the subsequent differentiation of the migratory cell. We will use a novel conditional inhibitor developed in our lab to understand how BMPs regulate these processes. The Xenopus tail has been shown to be a powerful system for studying the molecular basis of complex regenerative events. We have identified a TGF¿ superfamily ligand, GDF11, that controls outgrowth of the normal tail through the activation of Smad2. We plan to explore how GDF11 and Smad2 activation during tail regeneration interacts with other signaling pathways to establish the regenerative program. Understanding how extracellular factors control cell and tissue migration during normal development, during regenerative healing following extensive tissue damage, and during pathological processes such as tumor metastasis, provides a basis for new paths to therapeutic regulation of these events. The study of TGF¿ superfamily ligands provides a common approach, and a common set of molecular tools, with which to understand the regulation of these important physiological processes.