Mechanisms of cell competition that regulate growth during development

 描述(由申请人提供)：这项工作解决的中心问题是细胞如何传达它们的适应性，并识别可能危及生长组织的异常适应性差异。许多证据表明，对适应性差异的认识引发了相互作用，阻止了较弱的细胞对动物的贡献。这一过程被认为可以促进最佳的组织和组织健康。细胞竞争是促进这种动态平衡过程的一种机制，当细胞被更健壮的邻居认为它较少时，细胞竞争就开始了。不同适应度的细胞之间的竞争行为的例子很多，但最好的研究发生在一些核糖体蛋白(RP)或转录因子Myc的表达差异上。发育中的果蝇翅膀为研究细胞竞争提供了一个基本的、关键的范式。使用这个系统，我们最近发现，“赢家”和“输家”细胞之间的通信是由一种新的信号通路介导的，该信号通路由先天免疫通路中的成分组成。在这里，我们建议用实验来阐明这种信号机制的一个特定方面，即Spätzle(SPZ)的作用，这是一种分泌的细胞因子，我们认为它是消除这种信号机制所需的关键因素 在RP和Myc介导的细胞竞争中的失败者细胞。SPZ是一个NGF蛋白家族成员，具有一个关键的Cys结区，在果蝇胚胎的D/V模式和幼虫和成虫的先天免疫中，SPZ是Toll通路的激活配体。我们发现SPZ参与了细胞健康信息的传递，这一发现构成了这一应用的基础。果蝇在活体动物细胞间相互作用的镶嵌研究方面是无与伦比的，并提供无与伦比的遗传和分子工具包。这些信号通路的功能保守表明，解开它们在细胞竞争中的功能可能会对理解利用环境障碍生长如何导致癌症或疾病具有变革性意义。

 DESCRIPTION (provided by applicant): 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. This process is thought to promote 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 it by their more robust neighbors. Examples of competitive behavior between cells of different fitness are numerous, but the best studied occur from expression differences in one of a number of ribosomal proteins (Rp), or the transcription factor Myc. The developing Drosophila wing has provided an essential, key paradigm for study of cell competition. Using this system we recently discovered that communication between the "winner" and "loser" cells is mediated by a novel signaling pathway consisting of components co-opted from innate immune pathways. Here we propose experiments to elucidate a specific aspect of this signaling mechanism, the role of Spätzle (Spz), a secreted cytokine that we identified as a key factor required for the elimination of loser cells in both Rp- and Myc-mediated cell competition. Spz, an NGF protein family member characterized by a critical cys-knot domain, functions as an activating ligand for the Toll pathway in D/V patterning of the Drosophila embryo and in larval and adult innate immunity. Our discovery that Spz is involved in transmitting information about cell fitness forms the basis of this application. Drosophila is unsurpassed for mosaic studies of cell-cell interactions in living animals and offers unparalleled genetic and molecular toolkits. The functional conservation of these signaling pathways suggests that unraveling their functions in cell competition could be transformative for an understanding of how exploitation to environmental barriers to growth leads to cancer or disease.