The broad aim of this project is to use a combination of molecular, embryological, genetic and optical techniques to understand the cellular and molecular events that direct the morphogenesis of mesoderm within the mouse embryo. Our central hypothesis is that Wnt3a is a key signaling molecule essential for several aspects of mesoderm specification and patterning. Recent advances in the isolation of proteins that naturally fluoresce, and the refinement of techniques for optical microscopy offer unprecedented opportunities for in vivo imaging to study cellular and molecular events directly within embryos. The application of optical imaging combined with a novel panel of transgenic reporter expressing mice that we have generated represent a unique platform for acquiring quantitative information on cell behavior and cell fate in vivo. We will exploit these reagents to investigate the dynamic cell behaviors integral to the morphogenesis of the paraxial mesoderm in wild type embryos and an allelic series of Wnt3a mutants that disrupt this process.
The Specific Aims of this proposal are: (1) To use in vivo imaging to define the cell behaviors integral to the genesis of mesoderm within the primitive streak of the mouse embryo. (2) To use in vivo imaging to define the cell behaviors integral to the presomitic mesoderm. (3) To establish if paraxial mesoderm progenitor cells reside within the primitive streak of the mouse embryo. A role for signaling mediated by Wnt3a in these processes will be tested through use of the allelic series of Wnt3a mutants. This work will shed light on the cellular defects resulting from perturbations in mesoderm formation and will impact our understanding of the pathogenesis of human birth defects affecting the skeleton and musculature. Furthermore our work investigating mesodermal progenitor cells will contribute information towards the isolation of mesodermal stem cells, the determination of their intrinsic cell behaviors, their molecular signature and ultimately their directed differentiation for use in cell-based therapies. ? ? ?
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