The evolutionary and molecular mechanisms underlying sperm performance in an emer

描述(申请人提供)：有助于实验室小鼠繁殖成功的基因为哺乳动物生殖的分子、发育和生理过程提供了重要的见解，并作为研究人类不孕不育的模型。然而，与在自然界中观察到的变异程度相比，传统品系的实验室小鼠在生殖特征方面的变异程度有限。相比之下，与实验室小鼠关系密切的是Permyscus属的鹿小鼠，它们在生殖解剖、精子产生、形态和活动能力方面在物种之间表现出显著的差异。这种变异是由于属内交配系统的极端分化所致。在雌性在一个繁殖季节多次交配的物种中，不同雄性的精液之间存在着激烈的竞争，以求使其卵子受精。因此，在那里 在混杂物种中提高受精成功率的雄性生殖特征受到很大的选择压力；然而，在关系密切的一夫一妻制物种中，选择是宽松的。因此，Permyscus生殖性状的多样性使其成为研究雄性育性的遗传基础的有价值的模型，但此外，它们也为配子相互作用提供了一个全新的视角。当这些小鼠的精子被释放出来时，它们会形成合作单位--多个细胞在雌性生殖道内形成群体，这使它们能够比单个精子更具活力地游泳。在至少一个精子竞争最激烈的物种中，精子能够识别最相关的细胞，并选择性地与它们组合；事实上，这种细胞识别形式如此精致，以至于来自一只雄性的精子甚至可以区分精子和完整的同胞后代。相比之下，来自一夫一妻制物种的精子不分青红皂白地分组。这项拟议的研究旨在利用男性生殖特征的自然变异以及Permyscus精子独特的细胞识别和聚集行为来揭示影响受精成功的基因。该项目指导阶段的主要目标是利用与代表精子发生不同阶段的睾丸组织的基因表达研究相结合的遗传图谱，确定与精子活力和生殖成功相关的精子形态特征的遗传区域和最终影响基因。在这个项目的独立阶段，重点将放在探索精子聚集行为上，以了解群体是如何使用综合电子显微镜形成的，以及他们为什么会这样做--通过询问女性生殖道内和复杂环境中合作的精子迁移有什么影响？最后，随着对精子聚集的物理机制的了解，本研究将应用类似于指导阶段实施的遗传和基因组技术来揭示精子聚集大小的遗传基础以及参与精子细胞识别、识别和黏附的分子机制。总而言之，这项工作将为与男性生育能力相关的性状的遗传基础提供新的线索，并为配子识别和粘连提供一个独特的视角。 公共卫生相关性：了解男性生殖特征的遗传基础将为不孕不育和亚生育提供重要的见解，这是1/1的夫妇遇到的问题。此外，使用一种新的方法对选择性精子黏附进行仔细的机械、生理和分子表征将有助于我们对配子识别、黏附和交流的理解。这项工作集中在一种新兴的啮齿动物模型Permyscus小鼠中的自然变异表型，这为通常在实验室小鼠中进行的生育研究增加了一个新的视角，这些研究没有显示Permyscus精子所做的极端自然表型变异或选择性黏附，或者在人类中，在这些对照实验中是不可能的。

DESCRIPTION (provided by applicant): Genes contributing to reproductive success in laboratory mice have provided important insights into the molecular, developmental and physiological processes underlying mammalian reproduction and have served as models for studies of human infertility. Traditional strains of laboratory mice, however, are limited in the degree of variation in reproductive traits compared to the extent of variation observed in nature. In contrast, a close relative to the laboratory mouse, deer mice in the genus Peromyscus, exhibit striking differences in reproductive anatomy, sperm production, morphology and motility among species. This variation is due to the extreme divergence in mating system within the genus. In species in which females mate multiple times over a breeding season, there is intense competition between ejaculates of different males for fertilization of her eggs. Accordingly, there is strong selective pressure on male reproductive traits that improve fertilization success in promiscuous species; in closely-related monogamous species, however, selection is relaxed. Thus, the diversity of reproductive traits in Peromyscus makes them a valuable model for studies aimed at understanding the genetic basis of male fertility but, in addition, they also offe an entirely new perspective on gametic interactions. When sperm are released from these mice they form cooperative units-multiple cells form groups within the female reproductive tract, which enable them to swim with greater motility compared to individual sperm. In at least one species, the species in which sperm competition is most intense, sperm are able to recognize the most related cells and selectively group with them; in fact, this form of cellular recognition s so refined that sperm from one male can even discriminate against sperm from full sibling littermate. In contrast, sperm from a monogamous species group indiscriminately. The proposed study is designed to exploit the natural variation in male reproductive traits as well as the uniqu cellular recognition and aggregation behavior of Peromyscus sperm to reveal the genes that contribute to fertilization success. The primary goal in the mentored phase of this project is to identify genetic regions and ultimately genes influencing a morphological trait of sperm that is associated with motility and reproductive success using a genetic mapping approached combined with gene expression studies of the testicular tissue that represent different stages of spermatogenesis. During the independent phase of this project the focus will be on exploring sperm aggregation behavior to understand both how groups form using integrative electron microscopy and why they do - by asking what is the effect of cooperative sperm migration within the female reproductive tract and in complex environments? Finally, with an understanding of the physical mechanisms involved in sperm aggregation, this study will apply similar genetic and genomic techniques implemented in the mentored phase to reveal the genetic basis of sperm aggregate size and the molecular mechanisms involved in cellular recognition, discrimination and adhesion in sperm. In total, this work will shed new light on the genetic basis of traits associated with male fertility and offer a unique perspective on gametic recognition and adhesion. PUBLIC HEALTH RELAVANCE: Understanding the genetic basis of male reproductive traits will provide important insights into infertility and sub fertility, a problem encountered by 1 in 1 couples. Moreover, a careful mechanical, physiological and molecular characterization of selective sperm adhesion using a novel approach will inform our understanding of gamete recognition, adhesion and communication. This work focuses on naturally variable phenotypes in an emerging rodent model, Peromyscus mice, which adds a new perspective to fertility studies commonly performed in laboratory mice, which do not show the extreme natural phenotypic variation or selective adhesion that Peromyscus sperm do, or in humans, where such controlled experiments are not possible.