Mechanisms of cell competition that regulate growth during development

描述(申请人提供)：这项提案的总体目标是确定潜在的细胞竞争的分子机制，在这种机制中，当正常存活的细胞与生长速度更快的细胞相邻生长时，它们会通过凋亡被淘汰。在细胞竞争中，“失败者”细胞的损失被“胜利者”细胞的过度增殖所补偿，因此器官发育到具有适当细胞命运的正常大小。我们以前的工作表明，原癌基因c-myc的不同表达水平的细胞之间存在竞争，这种竞争在调节果蝇翅膀大小方面具有关键作用。是什么让一些细胞成为竞争的“赢家”，而另一些细胞则成为“输家”？基于我们以前的工作，我们假设dMyc诱导的细胞竞争是由一个短程信号介导的，该信号导致了“赢家”和“输家”的特定遗传程序。考虑到这一点，我们提出了一个系统的方法来识别潜在的细胞竞争的分子机制。使用体内翼盘模型系统和基于细胞培养的细胞竞争分析，我们在这里提出的实验将解决如何确定“成功者”和“失败者”细胞，以及关于它们的状态的信息如何在细胞群体之间交流。我们的主要目标是确定竞争细胞群体之间的基因表达差异，获得细胞竞争的遗传特征，识别细胞竞争发生所需的基因，并解决这些基因在竞争过程中的功能。由于细胞竞争在小鼠中也被记录在案，细胞竞争的机制及其在发育中的作用可能在苍蝇和脊椎动物之间保守。此外，Myc在许多癌症中的表达增加，因此这种机制也可以被早期肿瘤用来杀死附近的正常细胞并扩大它们的范围。我们推测，果蝇体内的细胞竞争可能提供了一种独特的模型，利用该模型可以识别参与癌症进展最早步骤的基因。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to identify the molecular mechanisms underlying cell competition, in which normally viable cells are eliminated via apoptosis when they grow next to cells with higher growth rates. During cell competition, the loss of the "loser" cells is compensated by extra proliferation of the "winners", thus the organ develops to a normal size with appropriate cell fates. Our previous work demonstrated that cells with different expression levels of the c-myc proto-oncogene ortholog dMyc compete with each other, and that this competition has a critical role in regulating Drosophila wing size. What makes some cells "winners" of the competition and other cells "losers"? Based on our previous work, we hypothesize that dMyc-induced cell competition is mediated by a short-range signal that leads to specific genetic programs in both the "winners" and the "losers". With this in mind, we propose a systematic approach to identify the molecular mechanisms underlying cell competition. Using both an in vivo wing disc model system and a cell-culture based cell competition assay, the experiments we propose here will address how "winner" and "loser" cells are determined, and how information about their status is communicated between the cell populations. Our primary objectives are to determine the gene expression differences between competing cell populations and obtain a genetic signature of cell competition, to identify genes that are required for cell competition to occur, and to address the function of these genes in the competitive process. Since cell competition has also been documented in the mouse, the mechanism of cell competition as well as its role in development is likely conserved between flies and vertebrates. Furthermore, Myc expression is increased in many cancers, thus such a mechanism could also be used by incipient tumors to kill off nearby normal cells and expand their territory. We postulate that cell competition in Drosophila may provide a unique model with which genes that are involved in the earliest steps of cancer progression can be identified.