DESCRIPTION (provided by investigator): Although the gestation period in mammals can last more than a year, it is rarely appreciated that the basic body plan of the embryo is established shortly after fertilization. In humans, the embryo establishes the three main body axes, the head to tail, dorsoventral and left/right axes, within the first two weeks of development. The importance of the early stages of embryogenesis for proper embryo development is underscored by the fact that thirty percent of human pregnancies are lost at early post-implantation stages. In previous studies, we have shown that the mouse conceptus is a dynamic and molecularly patterned structure. One major discovery is that the visceral endoderm, an extra-embryonic component, undergoes major rearrangements and is composed of several molecularly and morphologically distinct cell populations. These studies have pushed back the proven boundary of axial patterning in mice to 5.5 days post fertilization and more importantly, suggest that the visceral endoderm provides the blueprint for the establishment of the axes of the embryo. Using the mouse as a model system, we combine embryological, genetic and molecular approaches to investigate: (i) The relationship between the axes of pre- and post- implantation embryos; (ii) The role of the posterior visceral endoderm in the specification of the primitive streak, a structure that serves as a conduit for the generation of mesoderm and endoderm; (iii) The role of the visceral endoderm in the establishment of the primary heart field. Our central hypothesis is that the visceral endoderm has a major role in patterning the mouse embryo during early post-implantation stages and that these interactions are paramount for the initial stages of organogenesis. Our research will provide an understanding of the basic biology of the early mammalian embryo that serves as the foundation for the study of normal and abnormal human development. Project Narrative: The proposed studies are aimed at understanding the biology of mouse development during the initial stages of embryogenesis. We concentrate our studies in the role of the visceral endoderm, an extra- embryonic tissue, in the establishment of the three major axes of the embryo: the head to tail, dorsoventral and left-right axes. We also address the role of the visceral endoderm in the initial stages of heart development. Because development of the mammalian embryo is a hierarchical process, the events of early embryogenesis have profound consequences for the subsequent development of the organism. One of the main goals of our research is to determine if the basic body plan of the mammalian embryo is established at pre-implantation or post-implantation stages. Understanding this process is of major relevance in human procedures aimed at improving conception, such as intra-cytoplasmic sperm injection (ICSI). These procedures require extensive manipulation of gametes and culture of pre-implantation conceptuses that could cause birth defects. The study of axial development requires the understanding of the molecular bases of epithelial to mesenchymal transitions. This process is pivotal for the metastasis of carcinomas. Hence, our studies are relevant for cancer research. Finally, by understanding the initial stages of heart development, we provide the foundations for the development of approaches to generate myocardial cells.