Early development of mammalian embryos generates the extraembryonic cell lineages that provide nutritional and physical environments essential for embryonic survival. Project VI focuses on the development of extraembryonic mesoderm, one of three extraembryonic tissues formed during the peri-implantation period. Unlike trophoblast and extraembryonic endoderm lineages, which differentiate as single cell layers before implantation, extraembryonic mesoderm forms during gastrulation. Gastrulation is a complex morphogenetic process involving epithelial-mesenchymal transformation and cell migration, which transforms the epiblast layer into mesoderm, endoderm and ectoderm. Previous results of this Project strongly implicated extraembryonic mesoderm in the peri-implantation death of parthenogenetic embryos, owing to a failure of chorioallantoic fusion. The present study focuses on the origin, differentiation and morphogenesis of extraembryonic mesoderm, because this product of mammalian gastrulation is poorly understood. The Project begins by analyzing the mechanisms of mesoderm induction by peptide growth factors in peri-implantation embryos and pluripotent cells (Aim 1), continues by analyzing the roles of specific transcription factors as molecular determinants of extraembryonic mesoderm differentiation (Aim 2), and then integrates these findings with analysis of determination and other morphogenetic functions during extraembryonic mesoderm development (Aim 3). The hypothesis to be tested is that inductive events in early gastrulation are sufficient to specify an extraembryonic mesoderm fate. To approach this problem, in vitro explants of the epiblast layer will be studied to assess the effects of peptide growth factors--a mouse equivalent of the amphibian animal cap assay; gain-of-function and loss-of-function genetic transformation of embryos and pluripotent embryo-derived cells will be used to assess the role of specific growth factors; and transplantation of mesoderm cells between embryos will be used to assess their state of determination. together, these studies combine the genetic strengths of the mouse embryo system with amphibian-type experimental approaches to understand the development of this essential component of the chorioallantoic placenta. The results will contribute integrally to the Program theme on implantation and will have significant human health benefits, including implications for understanding syndromes of infertility and early pregnancy loss and inefficient implantation rates of embryos generated through medically assisted conception.
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