Mechanism of cell polarization and asymmetric segregation of ageing determinants

摘要：细胞不对称分裂是多种生物在组织和器官中分离衰老决定因子、分化细胞命运、形成不同细胞功能模式的基本机制。细胞极性的建立是不对称细胞分裂的关键初始事件，因为细胞极性指导细胞成分的分裂，并决定纺锤体和细胞分裂轴的方向1。近年来对芽殖酵母（Saccharomyces cerevisiae）在营养生长过程中经历不对称细胞分裂的研究，为揭示细胞极性和不对称细胞分裂的机制和设计原理提供了重要的见解。该项目的目标是阐明在细胞极性建立过程中对称性破坏的机制，并了解细胞极性轴如何允许衰老决定因素的分离，以实现“年轻”种群的持续更新。提出了三个具体目标。前两个目标集中在细胞极化的机制上，研究一个不涉及肌动蛋白细胞骨架的鲜为人知的细胞极化机制。我们计划验证Cdc42 GTPase（进化上保守的细胞极性主要调节因子之一）的自催化靶向和Cdc42 GTPase激活蛋白（gap）的延迟激活是肌动蛋白非依赖性对称破缺的关键机制的假设。第三个目标侧重于细胞极性如何指导新的和旧的多药耐药（MDR）蛋白的不对称分布。我们最近证明了一组MDR蛋白是酵母不对称分裂期间母体和芽之间不对称分离的重要衰老决定因素。该研究将测试极化蛋白翻译在新合成的MDR蛋白的不对称沉积中的可能作用，并将使用无偏倚的全基因组筛选来确定调节MDR蛋白不对称遗传的分子途径。

DESCRIPTION (provided by applicant): Mechanism of cell polarization and asymmetric segregation of ageing determinants Abstract: Asymmetric cell division is a fundamental mechanism employed in diverse organisms to segregate aging determinants, diversify cell fate, and form distinct patterns of cell function in tissues and organs. The established of cell polarity is a critical initial event in asymmetric cell division, as cell polarity directs the partitioning of cellular components and determines the orientation of the spindle and cell division axes1. Recent studies in the budding yeast Saccharomyces cerevisiae, which undergoes asymmetric cell division during its vegetative growth, have provided important insights into the mechanisms and design principles underlying cell polarity and asymmetric cell division. The goal of this project is to elucidate the mechanism of symmetry breaking during the establishment of cell polarity and understand how the axis of cell polarity allows segregation of aging determinants for the continuous renewal of a "youthful" population. Three specific aims are proposed. The first two aims center on the mechanism of cell polarization, investigating a poorly understood mechanism of cell polarization that does not involve the actin cytoskeleton. We plan to test the hypothesis that autocatalytic targeting of Cdc42 GTPase, one of the evolutionarily conserved, master regulators of cell polarity, and delayed activation of Cdc42 GTPase activating proteins (GAPs) are crucial mechanisms of the actin-independent symmetry breaking. The third aim focuses on how cell polarity directs asymmetric distribution of new and aged multi-drug resistance (MDR) proteins. We have recently demonstrated that a group of MDR proteins are important ageing determinants asymmetrically segregated between the mother and bud during yeast asymmetric divisions. The proposed study will test the possible role of polarized protein translation in the asymmetric deposition of newly synthesized MDR proteins and will use an unbiased genome-wide screen to identify the molecular pathways that regulate MDR protein asymmetric inheritance.