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: $ 9.76万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746539
• 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重要功能，涉及胚胎发育和组织稳态。它防止了来自不同区域的细胞的混合，其失败与病理状况（例如肿瘤转移）有关，癌细胞跨越边界并侵入相邻组织。我们提出，以裂缝状形态为特征的整个组织边界受保守的超模块控制，该模块将几个已知的信号通路或亚模块整合到独特的过程中。 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.基于自己的初步数据和已发布的结果，我们建议其他具有裂缝状结构的边界，Somite-Somite和Notochord-Somite边界也由此超模块控制。作为第一步，我们将研究爪蟾和斑马鱼胚胎中的脊索 - 汤岩（N-S）边界形成。我们将研究PAPC和SNAIL1在N-S边界形成中的作用的明显逆转只是一个实验性伪像，这是由于对这些因素在转录后水平上的表达的不同控制，还是基于其相互作用的实际重新连接。作为我们的第二个目标，我们将检查超模块的组成部分是否在N-S边界形成中表现出与外胚层 - 中胚层边界相同的上皮关系。此外，n-s边界形成发生在不同的组织环境中，即在背侧中胚层内而不是中胚层和外胚层之间，我们将询问如何将调节适应于这种新上下文。第三，我们将检查上面表征的调节模块是否在斑马鱼N-S边界形成中保守。实验方法和工具将与我们对爪蟾和斑马鱼中的外胚层 - 中胚层边界的研究一样。证明所提出的对照超模块的存在将简化包括人类在内的脊椎动物中组织边界的分类，分析和操纵。此外，我们的结果将阐明边界形成的演变，因为我们比较了两个不同脊椎动物的两个不同组织界面的相同过程。