ACTIVIN RECEPTORS AND SMAD2 IN MAMMALIAN GASTRULATION

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The transforming growth factor-beta (TGF-beta) superfamily molecules play critical roles in a diverse range of developmental processes. Our long term goal is to understand the signaling mechanism by which TGF-beta family factors regulate morphogenesis. Mesoderm induction and gastrulation are key events that lead to the establishment of body axes. Members of the TGF-beta family such as activins, Vg-1, nodal, and BMPs are potent mesoderm inducing factors and function during early development in vertebrate animals. The signaling cascade and the developmental program activated by activin or BMP has been extensively studied in Xenopus and chick early embryos. However, it remains unclear whether these signaling pathways are conserved in mammals. Genetic studies have demonstrated that nodal and BMP4, but not zygotic activins, are essential for early mouse development. To investigate the function of activin type I and type II receptors and a downstream signal mediator Smad2 in mammalian development, mutant mice have been generated by targeted disruption of the corresponding genes in mice. Genetic and embryological studies of the mutant mice have provided direct evidence that activin receptors and Smad2 are essential for mesoderm formation and gastrulation. To further analyze the function of activin receptor- and Smad2- mediated signaling pathways in the regulation of cell growth and differentiation, primitive streak formation and gastrulation, the following specific aims are proposed: (1) To understand how activin receptors and Smad2 regulate embryo growth, germ layer organization, and cell fate determination during egg cylinder formation and gastrulation. (2) To investigate how activin receptors and Smad2 regulate primitive streak formation and mesoderm patterning. 3) To investigate the function of nodal, BMP4, and chordin and their signaling pathways in primitive streak formation. Methods such as chimera (or mosaic) analysis through microinjection of blastocysts or aggregation of tetraploid embryos with ES cells, in situ hybridization, lineage analysis with lacZ-marked mutant ES cells, and ES cell-mediated gene delivery will be applied in this project. These aims, once accomplished, will lead to a better understanding of the signaling mechanism that controls early mammalian development. The knowledge acquired regarding early embryonic development will be useful for understanding later developmental processes such as organogenesis and will have important implications towards understanding the genetic basis of various forms of birth defects in human.