Mechanisms of Cell Competition in Growth and Development

项目摘要 这项工作解决的中心问题是细胞如何传递它们的健康和 认识到可能危及生长组织的异常适应性差异。很多证据 这表明，对健康差异的认识会引发相互作用，从而防止 较弱的细胞为动物做出贡献，促进组织和组织的最佳健康。 细胞竞争是一种促进这种动态平衡过程的机制，它是由 在识别出更健壮的邻居认为不太适合的细胞时。举例 不同适应度的细胞之间的竞争行为很多，但研究得最好的是 由减少的核糖体蛋白(RP)诱导，或降低或增强 转录因子Myc。发育中的果蝇翅是研究果蝇翅膀的重要范式 细胞竞争--作为一个模型系统，它在细胞-细胞镶嵌研究中是无与伦比的 并提供无与伦比的遗传和分子工具箱。我们 最近发现，“赢家”和“输家”细胞之间的交流是由 一种新的信号通路，由高度保守的 先天免疫反应途径。我们的长期目标是探索两者的近在咫尺(如何 这项工作)和关于细胞竞争的终极问题(它是为了什么)。在这项提案中，我们 重点关注三个主要任务：1)进一步探索信号激活的机制 控制并仅限于附近的“失败者”细胞；2)划定内源性角色 在正常动物生理过程中的细胞竞争；以及3)调查一种 细胞适应性感知的一般机制。

Project Summary The central problem this work addresses is how cells communicate their fitness and recognize aberrant fitness differences that might endanger growing tissues. Much evidence indicates that the recognition of fitness disparities elicits interactions that prevent the weaker cells from contributing to the animal, promoting optimal tissue and organismal fitness. Cell competition is a mechanism that facilitates this homeostatic process, and is initiated upon recognition of cells perceived as less fit by their more robust neighbors. Examples of competitive behavior between cells of different fitness are numerous, but the best studied those induced by reduced ribosomal proteins (Rp), or reduced or enhanced expression of the transcription factor Myc. The developing Drosophila wing is the critical paradigm for study of cell competition - as a model system it is unsurpassed for mosaic studies of cell-cell interactions in living animals, and offers unparalleled genetic and molecular toolkits. We recently discovered that communication between the “winner” and “loser” cells is mediated by a novel signaling pathway consisting of components co-opted from the highly conserved innate immune response pathways. Our long-term goal is to explore both proximate (how does this work) and ultimate (what is it for) questions about cell competition. In this proposal, we focus on three major quests: 1), to further explore the mechanism by which signal activation is controlled and restricted to only nearby “loser” cells; 2) to delineate the endogenous role of cell competition during normal animal physiology; and 3) to investigate the existence of a general mechanism of cell fitness sensing.