Post-translational regulation of sperm development and function in C. elegans

相关性：在正常和病理条件下，激酶和磷酸酶 细胞和发育途径的关键翻译后调节因子。调节不当 这些酶与从阿尔茨海默氏症、癌症到不育症多种病理学有关。 我们的研究将探讨与阿尔茨海默病相关激酶（tau）相关的激酶SPE-6 微管蛋白激酶和假磷酸酶SPE-54，这类酶的关键作用是 直到最近才被承认。原理：我们的研究将调查这些功能 蛋白质在C.精子发育和精子功能。因为 人类和C.秀丽线虫有许多相同的基因，在C.优雅可以是 与人类直接相关。相反，线虫特异性蛋白质需要生育力， 有希望的药物目标是消灭感染超过十亿人的线虫寄生虫。作为 实验系统，C.包括能够 通过其透明的身体监测精子在体内的迁移，使其成为一个优秀的模型 基础研究体系。此外，其精子发生的独特生物学 该计划为探索激酶和磷酸酶的功能提供了新的背景， 主要是在没有新基因转录的情况下。建议：拟议的研究将 探讨激酶SPE-6和假磷酸酶SPE-54的功能， 缺陷为研究大量未开发的细胞和发育提供了切入点 这种分析通常会产生生物学中的变革性见解。一是 研究SPE-6调节三种不同细胞的分子机制 途径：a）将线虫特异性细胞骨架蛋白组装成紧密堆积的纤维状结构， 体，B）精母细胞从生殖系合胞体中脱离，以及c） 染色体，以便它们可以在减数分裂期间分离。其次，我们将 使用体内和体外方法来研究SPE-54如何调节定向 精子向受精部位的移动性。调查结果应该广泛地告知我们的 了解激酶和假磷酸酶在不同细胞类型中的功能。

RELEVANCE: Under both normal and pathological conditions, kinases and phosphatases are key post-translational regulators of cellular and developmental pathways. Mis-regulation of these enzymes is associate with diverse pathologies from Alzheimer's and cancer to infertility. Our studies will investigate a kinase SPE-6 that is related to the Alzheimer's relevant kinase (tau tubulin kinase and a pseudophosphatase SPE-54, a class of enzymes whose critical roles are only recently being recognized. RATIONALE: Our studies will investigate the function of these proteins in the unique context of C. elegans sperm development and sperm function. Because humans and C. elegans share many of the same genes, discoveries made in C. elegans can be directly relevant to humans. Conversely, nematode-specific proteins required for fertility are promising drug targets for sterilizing nematode parasites that infect over a billion people. As an experimental system, the molecular and genetic tools of C. elegans including the ability to monitor sperm migration in vivo through its transparent body, make it an outstanding model system for fundamental research. Furthermore, the unique biology of its spermatogenesis program provides a novel context for exploring the function of kinases and phosphatases, largely in the absence of new gene transcription. OBJECTIVES: The proposed studies will explore the functions of a kinase SPE-6 and a pseudophosphatase SPE-54 whose phenotypic defects provide an entry point for investigating largely unexplored cellular and developmental pathways as such analysis often generates transformative insights in biology. First, we will investigate the molecular mechanisms by which SPE-6 regulates three distinct cellular pathways: a) assembly of a nematode specific cytoskeletal protein into tightly packed fibrous bodies, b) detachment of spermatocytes from the germline syncytium, and c) the remodeling of chromosomes so that they can be segregated during the meiotic divisions. Secondly, we will use both in vivo and in vitro approaches to investigate how SPE-54 regulates the directed mobility of the sperm to the site of fertilization. The findings should broadly inform our understanding of kinase and pseudophosphatase functions in diverse cell types.