Person: Rogers, Katherine Wallace
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Katherine Wallace
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Rogers, Katherine Wallace
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Publication Mesendoderm Patterning by the Nodal/Lefty Activator/Inhibitor System(2015-01-16) Rogers, Katherine Wallace; Needleman, Daniel; Reddien, PeterDuring zebrafish embryogenesis, a gradient of the secreted TGFβ ligand Nodal induces expression of mesendodermal genes in an exposure-dependent manner, and also induces expression of the secreted Nodal feedback inhibitor Lefty. The long-range Lefty gradient dampens signaling by the shorter-range Nodal gradient, and together they are required for proper patterning of the germ layers. My research has addressed two fundamental questions about this patterning system: 1) How are the distinct ranges of Nodal and Lefty achieved, and 2) What is the role of Lefty-mediated feedback inhibition in this patterning system? To understand why Nodal and Lefty have different activity ranges, we developed fluorescent fusion proteins and microscopy techniques to measure the distributions, degradation rates, and diffusion coefficients of Nodal and Lefty in living zebrafish embryos. We found that Nodal-GFP forms a shorter-range gradient than Lefty-GFP in vivo, consistent with the shorter activity range of Nodal. The extracellular half-lives of Nodal-Dendra2 and Lefty-Dendra2 are similar, but the diffusion coefficient of Nodal-GFP is much lower than that of Lefty-GFP. Differential diffusivity therefore explains the shorter range of Nodal compared to Lefty. To better understand the function of Lefty during vertebrate embryogenesis, we generated and analyzed zebrafish lefty mutants. Although patterning is highly robust to lefty gene dosage, complete loss of lefty causes upregulation of mesendodermal genes during gastrulation, aberrant cell internalization, and severe patterning defects, consistent with excess Nodal signaling. Mutations in nodal partially suppress patterning defects caused by lefty loss, and lefty mutants can be fully rescued by ectopic expression of lefty-gfp or by treatment with low levels of a Nodal inhibitor drug. Further, lefty expression is highly responsive to Nodal signaling. These results demonstrate that Lefty acts as a fast-responding, global dampener of Nodal signaling that restricts mesendoderm specification.