Defining Direct and Indirect Roles of Nodal Signaling in Convergence & Extension

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Project Summary Extension of the anterior-posterior (head to tail) body axis is critical to development of a healthy fetus. Defects in this process can result in abnormally short embryos, and more importantly, neural tube closure defects (NTDs). NTDs affect approximately 1 in 1,000 human births, making them one of the most common classes of congenital birth defects. Despite the significant burden to individuals and society the underlying genetic causes remain still poorly understood. Therefor, defining the mechanisms of axis extension contributes significantly to the fundamental study of developmental biology and has important implications in human health. Anterior- posterior (AP) axis extension occurs via a highly conserved morphogenetic mechanism called convergence and extension (C&E), which employs polarized cell behaviors such as directed migration and ML cell intercalation to drive mediolateral (ML) narrowing of the body accompanied by elongation in the AP dimension. In vertebrate embryos, this occurs during gastrulation, the early embryonic process during which the three primordial germ layers are established and then shaped into a rudimentary body plan. Patterning of the AP axis is also required, and in some cases sufficient, for C&E to occur. AP positional identity of a tissue is established during embryonic axis patterning prior to the onset of gastrulation, but how this is communicated to the morphogenetic machinery that drives C&E is not understood. This coordination of tissue patterning with morphogenesis remains one of the most fundamental questions in developmental biology. The morphogen Nodal likely occupies a vital position at the interface of tissue patterning and morphogenesis. In vertebrate embryos, graded Nodal signaling is essential for induction of endoderm and mesoderm and AP patterning, with higher Nodal levels specifying more dorsal/anterior cells fates. Loss of Nodal signaling in zebrafish embryos results in severely reduced axial extension and an open neural tube, but also nearly complete mesoderm deficiency, making it unclear whether extension defects in the neuroectoderm are due directly to the loss of Nodal signaling or indirectly to the loss of mesoderm. Experimental evidence suggests an instructive yet indirect role of Nodal signaling during C&E of mesodermal tissues, but the way(s) by which Nodal signaling regulates C&E is unknown. Here, I propose to test the hypothesis that Nodal signaling regulates C&E gastrulation movements indirectly via its role in mesoderm specification and patterning, and aim to define the tissue, cellular, and molecular mechanisms by which Nodal signaling provides instructive cues for axis extension. Characterization of Nodal's role in this process will significantly increase our understanding of how tissue patterning is coordinated with morphogenesis in vertebrate embryos and can help to identify the underlying causes of NTDs.