ErbB signaling in vertebrate morphogenesis

这项拟议研究的总体目标是了解ErbB信号如何调节细胞黏附和 脊椎动物早期发育过程中的运动。非洲爪哇原肠繁殖将作为模型系统用于 这项研究。 ErbB信号涉及四个相关的受体酪氨酸激酶(ERBbs)，它们介导表皮的作用 生长因子(EGF)及其相关生长因子。它最为人所知的是它在癌症中的作用，因为它在 EGF样配体和ErbB受体都与癌症的形成和发展有关。而当 ErbB信号在细胞增殖和肿瘤生长中的作用已被广泛研究，ErbB的作用机制 对癌症转移中的信号转导知之甚少。在脊椎动物早期发育过程中，ErbB信号是 已知可调节多种过程，包括心脏形态发生、神经突起延伸和神经元 迁移。ErbB信号控制细胞形态和/或运动的方式 流程不被理解。 该实验室的初步研究表明，除了调节癌症和癌症中的细胞行为外， 在心脏和神经发育中，ErbB信号也控制着早期原肠形成期间的细胞运动 青蛙胚胎。原肠形成是中胚层和内胚层被置于 胚胎形成内部组织和器官。在这个过程中协调的细胞运动确保适当的 脊椎动物身体计划的形成。ErbB信号调节原肠形态发生，但详细的 机制还不清楚。这笔赠款旨在检验这样一种假设，即 酪氨酸激酶在ErbB受体下游被激活，通过 细胞黏附复合体的修饰。在目标1中，这些细胞质酪氨酸激酶通路在 我们将研究ErbB依赖的原肠形成运动。在目标2中，ErbB-Src/ErbB-Abl的作用 关于肌动蛋白细胞骨架动态组织的信号将被研究。从这些数据中获得的结果 研究将为ErbB信号控制原肠形成和生长的机制提供重要的见解。 将有助于阐明ErbB信号如何在其他环境中调节细胞行为，例如在 哺乳动物胚胎发育过程中的肿瘤转移和细胞运动。

The overall goal of the proposed research is to understand how ErbB signaling regulates cell adhesion and movements during early vertebrate development. Xenopus gastrulation will be used as the model system in this study. ErbB signaling involves four related receptor tyrosine kinases (ErbBs) that mediate actions of epidermal growth factor (EGF) and its related growth factors. It is best known for its function in cancer, as mutations in both EGF-like ligands and ErbB receptors are implicated in cancer formation and progression. While the roles of ErbB signaling in cell proliferation and tumor growth are well studied, the mechanisms of ErbB signaling in cancer metastasis are less understood. During early vertebrate development, ErbB signaling is known to modulate multiple processes, including heart morphogenesis, neurite extension and neuronal migration. The means via which ErbB signaling controls cell morphology and/or movements in these processes are not comprehended. Preliminary studies from this laboratory demonstrate that in addition to modulate cell behaviors in cancer and in heart and neural development, ErbB signaling also controls cell movements during gastrulation in early frog embryos. Gastrulation is the process through which mesoderm and endoderm are placed inside the embryos to form internal tissues and organs. Coordinated cell movements during this process ensure proper formation of the vertebrate body plan. ErbB signaling regulates gastrulation morphogenesis, but the detailed mechanisms are not understood. This grant is intended to examine the hypothesis that Src and Abl families of tyrosine kinases are activated downstream of ErbB receptors to regulate gastrulation movements via modification of cell adhesion complexes. In aim 1, the roles of these cytoplasmic tyrosine kinase pathways in ErbB-dependent gastrulation movements will be examined. In aim 2, the effects of the ErbB-Src/ErbB-Abl signals on the dynamic organization of actin cytoskeleton will be investigated. Results obtained from these studies will provide crucial insight into the mechanisms via which ErbB signaling controls gastrulation and will help to shed light on how ErbB signaling may modulate cell behaviors in other contexts, such as in cancer metastasis and in cell movements during mammalian embryogenesis.