The molecular basis of allorecognition and its roles in development and evolution of the social amoeba D. discoideum

 描述(申请人提供)：异体识别被定义为生物体区分自我和非我的能力，这是许多生物体的共同主题，也是多细胞进化和合作的中心组成部分。在哺乳动物中，异体识别是由主要组织相容性复合体(MHC)介导的，MHC是免疫系统的一部分。MHC有助于在移植医学中识别感染过程中的寄生虫和移植物排斥反应。有证据表明其他蛋白质参与了移植物排斥反应，但可用于研究这些蛋白质的模型系统很少。在非哺乳动物系统中，特别是在海洋生物中，有许多同种异体识别系统，但它们中的大多数都不适合用分子遗传工具进行操作。我们在社会土壤中发现了一种同种异体识别系统，为从分子和细胞到组织、基因组和社会等不同水平上的同种异体识别与合作概念的分子遗传学探索打开了新的领域。Dictyostelials异体识别系统是基于两种蛋白质TgrB1和TgrC1，这两种蛋白质与哺乳动物的MHC蛋白有许多共同的性质，但它们的氨基酸序列不同。这些跨膜蛋白在自然种群中是高度多态的，它们是识别同种异体所必需的，也是充分的。当食物充足时，网柄基菌细胞在土壤中以游离阿米巴的形式生活，但当饥饿时，它们会聚集成多细胞有机体。聚集涉及对细胞外cAMP的趋化作用，而网状网柄菌是研究趋化作用的最佳模型系统之一，趋化作用是胚胎发育和先天免疫的核心过程。当网柄菌细胞在聚集过程中遇到携带不相容的TgrB1和TgrC1的细胞时，它们彼此分离，形成单独的多细胞有机体。这种隔离保护细胞免受作弊者的伤害，作弊者是指在不支付全部合作成本的情况下利用社会福利的个人。我们认为，一个细胞表面的TgrB1与相邻细胞表面的TgrC1结合，这种结合启动了改变细胞行为的信号转导级联反应。我们计划从四个层面对这一系统进行调查。在蛋白质水平上， 我们将探索定义TgrB1-TgrC1结合亲和力和特异性的属性，以及介导下游信号转导的机制。在细胞水平上，我们将研究TgrB1与TgrC1结合后立即传递同种识别信号的途径，导致趋化性和细胞极性的变化。在发育水平，我们将研究细胞从不相容的细胞中分离出来并与相容的细胞合作形成组织后，改变基因表达和细胞生理的长期事件。在基因组水平上，我们感兴趣的是这两个发育必需基因如何共同进化并在种群中保持多态。

 DESCRIPTION (provided by applicant): Allorecognition is defined as the ability of organisms to distinguish self from non-self, a common theme in many organisms and a central component in the evolution of multicellularity and cooperation. In mammals, allorecognition is mediated by the Major Histocompatibility Complex (MHC), which is part of the immune system. The MHC facilitates identification of parasites in infection processes and graft rejection in transplantatin medicine. There is evidence for the involvement of other proteins in graft rejection but there are very few model systems available to study these proteins. There are numerous allorecognition systems in non- mammalian systems, notably in marine organisms, but most of them are not amenable to manipulation with molecular genetic tools. We have found an allorecognition system in the social soil amoeba Dictyostelium discoideum, opening the field to molecular genetic exploration of concepts in allorecognition and cooperation at various levels - from molecules and cells to tissues, genomes and societies. The Dictyostelium allorecognition system is based on two proteins, TgrB1 and TgrC1, that share many properties with mammalian MHC proteins, but not their amino acid sequences. These trans-membrane proteins are highly polymorphic in natural Dictyostelium populations and they are necessary and sufficient for allorecognition. Dictyostelium cells live as free amoebae in the soil when food is abundant but they aggregate into multicellular organisms when starved. Aggregation involves chemotaxis to extracellular cAMP and Dictyostelium is one of the best model systems for the study of chemotaxis, which is a central process in embryogenesis and in innate immunity. When Dictyostelium cells encounter cells that carry incompatible TgrB1 and TgrC1 during aggregation, they segregate from one another and form separate multicellular organisms. This segregation protects cells from cheaters, which are individuals that take advantage of social benefits without paying the full cost of cooperation. We propose that TgrB1 on the surface of one cell binds TgrC1 on the surface of an adjacent cell and that binding initiates a signal transduction cascade that alters cell behavior. We plan to investigate this system at four levels. At the protein level, we will explore the properties that define TgrB1-TgrC1 binding affinity and specificity and the mechanisms that mediate downstream signal transduction. At the cell level, we will study the pathways that transduce the allorecognition signals immediately after TgrB1 binds TgrC1, leading to changes in chemotaxis and cell polarity. At the developmental level, we will study the long-term events that change gene expression and cell physiology after cells segregate from incompatible cells and cooperate with compatible cells to form tissues. At the genome level, we are interested in how the two developmentally essential genes co-evolve and maintain polymorphism in the population.