Thursday, December 26, 2024
12/26/2024
ABSTRACT The overall goal of this Maximizing Investigator’s Research Award renewal application is to advance understanding of how inductive and morphogenetic processes during vertebrate embryogenesis are coordinated to ensure normal development. Early inductive processes controlled by maternal and zygotic gene products establish embryonic polarity and germ layers, while convergence and extension (C&E) gastrulation movements elongate embryonic tissues down the anteroposterior axis and narrow them mediolaterally. The noncanonical Wnt/Planar Cell Polarity (Wnt/PCP) signaling pathway polarizes morphologies and behaviors of mesenchymal gastrula cells that shape embryonic body. We previously proposed that Wnt/PCP signaling acts as a cellular compass that orients cells with respect to the anteroposterior embryonic axis, but how the compass is regulated is not understood. During the previous funding period, we surprisingly found that several pathways work in parallel to Wnt/PCP to polarize cells during C&E. We also implicated in C&E another conserved regulator of planar polarity, Dachsous atypical cadherin, which is essential for many processes, including embryonic cleavages and axis specification, by promoting microtubule dynamics. We invested significant effort in generating new genetic tools to probe the mechanisms of the Wnt/PCP compass and initiated a genetic screen for new gastrulation regulators. These findings and tools motivate our future studies in three research themes. In the first, we will investigate how numerous membrane receptors, including Gpr125 adhesion GPCR, which we implicated in the Wnt/PCP compass, interact during C&E. Using precise mutations and tags in the endogenous gpr125 locus, proteomic and genetic experiments, we will test whether Gpr125 promotes formation of Wnt/PCP complexes composed of select components. In the second theme, we will extend our studies of Dachsous and investigate whether it regulates gastrulation movements by promoting microtubule dynamics. Using Dachsous endogenously tagged with GFP, we will carry out proteomic studies to isolate endogenous interactors, and genome editing to define its critical regions. In a parallel unbiased genetic approach, we will continue a promising genetic screen for maternal and maternal-zygotic mutations that impair embryogenesis and gastrulation. Altogether, our mechanistic studies of Wnt/PCP and Dachsous regulators of planar cell polarity and unbiased genetic screens, will both advance the MIRA mission and understanding how inductive and morphogenetic processes are coordinated during vertebrate gastrulation. As mutations in the components of these pathways cause miscarriages, birth defects and diseases, our studies will provide insights into their understanding and diagnosis, and facilitate development of therapies.
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