The Molecular Basis of Allorecognition in Social Amoeba

自我/非自我认知是生活的一个基本方面。细胞合作的进化导致了组织， 器官和多细胞生物被认为需要发展强大的机制， 自我/非自我识别，或异体识别，以防止遗传上不同的竞争对手的剥削。的 社会性变形虫，盘状网柄阿米巴，是一个很好的模型系统，其中细胞粘附，信号传导和 发育过程中的组织形成已经被广泛研究， 工具已经开发出来。我们认为细胞在D. 盘状突发育，以通过有利于同种异体识别的过程来优化细胞合作， 在遗传上相关的个体之间的公共孢子形成。D.盘突显示 合作行为与他们的遗传亲缘关系成正比，我们发现了一个家庭， 这些蛋白质可能构成了这种合作的分子基础。这个想法是基于我们的发现 粘附蛋白LagC1和相关蛋白LagB1是细胞合作所需的 为了将细胞整合到多细胞组织中，它们的基因是共同调节的，两者都显示出阳性或阴性的证据。 平衡选择，暗示适应性进化，它们的序列多态性与 同种识别LagC1型基因在人类基因组中也是丰富和多态的， 这表明我们在网骨藻中发现的机制将与人类相关并适用于人类 发育和先天免疫。我们假设高度多态性的膜蛋白可能介导 一般来说，同种识别，以及特异性蛋白质LagB1和LagC1在功能上相互作用以介导 通过等位基因特异性细胞间粘附和信号传导进行同种异体识别，从而有利于协同 基因相似个体的孢子形成。为了验证这些假设，我们将搜索 基因组中编码多态性跨膜蛋白的基因，并测试它们与 野生株之间的同种识别（分离）。我们将进一步研究最相关的蛋白质的作用 在使用诱变和基因置换方法的同种异体识别中， LagB1和LagC1在此过程中的具体作用。

Self/nonself recognition is a fundamental aspect of life. The evolution of cellular cooperation that led to tissues, organs and multicellular organisms is thought to have required the development of robust mechanisms of self/nonself recognition, or allorecognition, to preclude exploitation by genetically dissimilar competitors. The social amoeba, Dictyostelium discoideum, is an excellent model system in which cell adhesion, signaling and tissue formation during development have been studied extensively and for which powerful molecular genetic tools have been developed. We propose that cells integrate adhesion and communication during D. discoideum development to optimize cellular cooperation through a process of allorecognition that favors communal sporulation between genetically related individuals. Wild isolates of D. discoideum display cooperative behavior that is directly proportional to their genetic relatedness and we have uncovered a family of proteins that may form part of the molecular basis for this cooperation. This idea is based on our findings that the adhesion protein LagC1 and the related protein LagB1 are required for the cellular cooperation needed to integrate cells into a multicellular tissue, their genes are co-regulated, both display evidence of positive or balancing selection, suggestive of adaptive evolution, and their sequence polymorphism correlates well with allorecognition. Genes of the LagC1 type are abundant and polymorphic in the human genome as well, suggesting that the mechanisms we find in Dictyostelium would be relevant and applicable to human development and innate immunity. We hypothesize that highly polymorphic membrane proteins may mediate allorecognition in general, and that the specific proteins LagB1 and LagC1 interact functionally to mediate allorecognition through allele-specific intercellular adhesion and signaling, thus favoring cooperative sporulation of genetically similar individuals. To test these hypotheses, we will search the Dictyostelium genome for genes that encode polymorphic transmembrane proteins and test their correlation with allorecognition (segregation) between wild strains. We will further study the role of the most correlated proteins in allorecognition using mutagenesis and gene replacement approaches following the example of studying the specific roles of LagB1 and LagC1 in the process.