Transforming growth factor-beta (TGF beta) superfamily molecules have essential roles in a myriad of biological processes including oncogenesis, immunity, differentiation, and development. This application examines the subset of developmental biology that considers how cell fates are specified as well as how the body plan is generated during vertebrate embryogenesis. The molecular mechanisms that underlie the transition from a radially symmetric egg to a patterned embryo remain largely unknown. What appears clear is that embryonic cells send signals that instruct neighboring cells to change fate in a process known as induction. These inductive interactions appear to be mediated by peptide growth factors and members of the TGF beta superfamily are among the best candidates for the role of endogenous inducing signals. However, little is known about the signaling cascade of TGF beta signals. Genetic studies in Drosophila identified the Smad family as components of TGF beta superfamily signaling. Our preliminary experiments have demonstrated that Smad homologues are present in vertebrates, are expressed at the appropriate time to play a role in formation of the vertebrate body plan, and probably function during embryogenesis. We propose to study the endogenous role of the members of the Smad family in early vertebrate development using Xenopus laevis as a model system. The specific experimental aims area: I. To determine the temporal and spatial expression pattern of maternally expressed Smads. II. To characterize the signals responsible for induction and morphogenesis. III. To analyze the post-translation modifications of the Smads as markers to reflect activation of endogenous inducting signals in vivo. IV. To characterize the specificity of induction. The medical significance of these studies derives from a better understanding of both the Smad family and TGF beta signaling. The Smads have recently been identified as tumor suppressor genes and TGF beta molecules have a myriad of effects including roles in oncogenesis, inflammation, immunity, and reproduction.
| Clegg, Deborah J; Palmer, Biff F (2013) Effects of an estrogen receptor ? variant. N Engl J Med 369:1663-4 |
| McKay, R M; Peters, J M; Graff, J M (2001) The casein kinase I family: roles in morphogenesis. Dev Biol 235:378-87 |
| McKay, R M; Peters, J M; Graff, J M (2001) The casein kinase I family in Wnt signaling. Dev Biol 235:388-96 |
| Fortuno 3rd, E S; LeSueur, J A; Graff, J M (2001) The amino terminus of Smads permits transcriptional specificity. Dev Biol 230:110-24 |
| Scherer, A; Graff, J M (2000) Calmodulin differentially modulates Smad1 and Smad2 signaling. J Biol Chem 275:41430-8 |
| LeSueur, J A; Graff, J M (1999) Spemann organizer activity of Smad10. Development 126:137-46 |
