A conserved control module for cleft-like tissue boundary formation in the vertebrate embryo

脊椎动物胚胎中裂隙样组织边界形成的保守控制模块

• 批准号: RGPIN-2017-06667
• 负责人: Winklbauer, Rudolf
• 金额: $ 4.88万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=712333
• 关键词: conserved; control; module; cleft; like

The formation and maintenance of tissue boundaries is an essential function in all animals, and involved in embryonic development and tissue homeostasis. It prevents the intermingling of cells from different regions, and its failure is associated with pathological conditions such as tumour metastasis where cancer cells cross boundaries and invade adjacent tissues. We propose that a whole class of tissue boundaries, characterized by a cleft-like morphology, are controlled by a conserved super-module that integrates several known signaling pathways or sub-modules into a unique process. Studying tissue separation between ectoderm and mesoderm germ layers in the Xenopus and zebrafish embryo, we found that a combination of Eph/ephrin signaling, Snail1-activated paraxial protocadherin (PAPC) function, and inhibition of planar cell polarity signaling by PAPC is necessary for the formation of the cleft-like ectoderm-mesoderm boundary. Based on own preliminary data and on published results, we propose that other boundaries with a cleft-like structure, the somite-somite and the notochord-somite boundaries, are also controlled by this super-module. As a first step, we will study notochord-somite (N-S) boundary formation in Xenopus and zebrafish embryos. We will examine whether an apparent reversal of the roles of PAPC and Snail1 in N-S boundary formation is only an experimental artifact, due to a different control of the expression of these factors at the post-transcriptional level, or whether it is based on an actual re-wiring of their interaction. As our second aim, we will examine whether the components of the super-module show the same epistatic relations in N-S boundary formation as at the ectoderm-mesoderm boundary. Moreover, N-S boundary formation occurs in a different tissue context, i.e. within the dorsal posterior mesoderm instead of between mesoderm and ectoderm, and we will ask how regulation is possibly adapted to this new context. Third, we will examine whether the regulatory modules characterized above are conserved in zebrafish N-S boundary formation. Experimental approaches and tools will be as in our studies of the ectoderm-mesoderm boundary in Xenopus and zebrafish. Demonstrating the existence of the proposed control super-module would simplify the categorization, analysis and manipulation of tissue boundaries in vertebrates including humans. In addition, our results will shed light on the evolution of boundary formation as we compare the same process at two different tissue interfaces in two different vertebrates.

组织边界的形成和维持是所有动物的一项重要功能，并参与胚胎发育和组织稳态。它可以防止来自不同区域的细胞混合，其失败与病理状况有关，例如癌细胞跨越边界并侵入邻近组织的肿瘤转移。我们提出，以裂隙状形态为特征的一整类组织边界是由保守的超级模块控制的，该超级模块将几个已知的信号通路或子模块集成到一个独特的过程中。研究非洲爪蟾和斑马鱼胚胎中外胚层和中胚层胚层之间的组织分离，我们发现 Eph/ephrin 信号传导、Snail1 激活的旁轴原钙粘蛋白 (PAPC) 功能以及 PAPC 对平面细胞极性信号传导的抑制的组合对于分离是必要的。裂状外胚层-中胚层边界的形成。根据自己的初步数据和已发表的结果，我们提出具有裂隙状结构的其他边界，体节-体节和脊索-体节边界，也由该超级模块控制。第一步，我们将研究爪蟾和斑马鱼胚胎中脊索体节（N-S）边界的形成。我们将研究 PAPC 和 Snail1 在 N-S 边界形成中的作用的明显逆转是否只是一个实验假象，因为这些因子在转录后水平的表达控制不同，或者是否基于实际的结果。重新布线他们的互动。作为我们的第二个目标，我们将检查超级模块的组件在 N-S 边界形成中是否表现出与外胚层-中胚层边界相同的上位关系。此外，N-S边界的形成发生在不同的组织环境中，即在背侧后中胚层内而不是在中胚层和外胚层之间，我们将询问调节如何可能适应这种新环境。第三，我们将检查上述特征的调节模块在斑马鱼南北边界形成中是否保守。实验方法和工具将与我们对爪蟾和斑马鱼的外胚层-中胚层边界的研究一样。证明所提出的控制超级模块的存在将简化包括人类在内的脊椎动物组织边界的分类、分析和操作。此外，当我们比较两种不同脊椎动物的两个不同组织界面的相同过程时，我们的结果将揭示边界形成的演变。