Control of Cell Differentiation: Inhibition of Sperm Activation in C. elegans

细胞分化的控制：线虫精子激活的抑制

• 批准号: 7803585
• 负责人: CRAIG W LAMUNYON
• 金额: $ 10.65万
• 依托单位: CALIFORNIA STATE POLY U POMONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803585
• 关键词: Address; Affect; Alzheimer' s Disease; Appearance; Applications Grants; Biochemical; Bioinformatics; Bypass; Caenorhabditis elegans; Cell Differentiation Inhibition; Cell Proliferation; Cell division; Cells; Cellular Morphology; Characteristics; Code; Collection; DNA Sequence; DYSF gene; Data; Development; Disease; Event; Exocytosis; Failure; Funding; Future; Gene Expression; Gene Family; Genes; Genetic; Genetic Complementation Test; Genetic screening method; Goals; Health; Homologous Gene; Human; Individual; Investigation; Knowledge; Laboratories; Lead; Limb-Girdle Muscular Dystrophies; Location; Malignant Neoplasms; Maps; Membrane; Modeling; Molecular; Muscle function; Muscular Dystrophies; Mutate; Mutation; Nematoda; Neurodegenerative Disorders; Neuromuscular Diseases; Neurons; Pathway interactions; Play; Positioning Attribute; Proteins; Pseudopodia; Regulation; Regulatory Pathway; Research; Research Project Grants; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Spermatids; Spermiogenesis; System; Testing; Vesicle; Work; base; gene function; genetic analysis; insight; member; mutant; premature; presenilin-1; prevent; public health relevance; repaired; sperm cell

DESCRIPTION (provided by applicant): Cellular events typically require precise regulatory control. Regulation failures may lead to problems like uncontrolled cellular proliferation and cancer. The regulation of spermiogenesis in the model nematode Caenorhabditis elegans is the focus of the proposed research, and it has the potential to provide insight into the workings of genes homologous to those involved in Alzheimer's disease and to aid in understanding regulated vesicle exocytosis, an event important in neuronal function and muscle membrane repair. During spermiogenesis, the spherical spermatid undergoes a dramatic reorganization to form an amoeboid spermatozoon. Spermiogenesis involves cytoskeletal and membrane reorganization and vesicle exocytosis, yet it occurs without new gene expression, employing only preexisting cellular components. As with other cellular systems, the regulation of spermiogenesis in C. elegans involves both positive and negative controls, but the negative regulation that inhibits spermiogenesis is poorly understood. The research proposed here will characterize the genes involved in spermiogenesis inhibition by examining a collection of ten mutants that fail to inhibit spermiogenesis properly. Preliminary data indicate that three of the mutations in this collection map to unique loci that do not correspond to known sperm genes. These mutations define genes involved in spermiogenesis inhibition, and the aims of the proposed research are to: (i) identify and clone the spermiogenesis inhibition genes in this collection; and (ii) characterize the functions of the identified genes. To accomplish these aims the mutations will be genetically mapped using molecular and morphological markers. The coding sequence affected by at least two, but perhaps as many as four of the mutations will be identified using a combination of approaches that include DNA sequencing, transformation rescue, and complementation tests. Phenotypic, genetic, and bioinformatic analyses will provide information on the mechanism of action for the gene products. The proposed research is significant because it will enable both a comprehensive understanding of the regulation of spermiogenesis in C. elegans specifically and a better understanding of vesicle exocytosis in general. Indeed, the mutant collection to be studied here has already been fruitful in providing information on the human neurodegenerative disease gene homolog spe-4 (Alzheimer's disease), showing it inhibits spermiogenesis. Public Health Relevance: The regulation of spermiogenesis in C. elegans has very significant relevance to human health. Because spermiogenesis shares characteristics with regulated vesicle exocytosis in humans, the proposed research will aid in understanding regulated exocytosis. In addition, this research has the potential to provide insight into the workings disease gene homologs, such as spe-4 (Presenilin-1; Alzheimer's disease) and fer-1 (Dysferlin family genes; muscular dystrophy).

描述（由申请人提供）：细胞事件通常需要精确的调节控制。调控失败可能导致诸如不受控制的细胞增殖和癌症等问题。模型线虫秀丽隐杆线虫精子发生的调控是本研究的重点，它有可能为了解与阿尔茨海默病相关的同源基因的工作提供见解，并有助于理解调控的囊泡胞吐，这是神经元功能和肌肉膜修复的重要事件。在精子发生过程中，球形精子经过剧烈的重组形成变形虫精子。精子发生涉及细胞骨架和膜的重组以及囊泡的胞外分泌，但它的发生没有新的基因表达，只使用预先存在的细胞成分。与其他细胞系统一样，秀丽隐杆线虫的精子发生调控包括正调控和负调控，但对抑制精子发生的负调控知之甚少。这里提出的研究将通过检查10个不能正确抑制精子发生的突变体来描述参与精子发生抑制的基因。初步数据表明，该集合中的三个突变映射到与已知精子基因不对应的独特位点。这些突变定义了与精子发生抑制有关的基因，拟议研究的目的是：(i)鉴定和克隆该集合中的精子发生抑制基因；（ii）鉴定鉴定基因的功能。为了实现这些目标，将利用分子和形态标记对突变进行遗传定位。编码序列至少受两种，但可能多达四种突变的影响，将使用包括DNA测序，转化拯救和互补测试在内的方法组合来确定。表型、遗传和生物信息学分析将为基因产物的作用机制提供信息。这项研究具有重要意义，因为它将使我们能够全面了解秀丽隐杆线虫精子发生的具体调控，并更好地了解囊泡胞外分泌的一般情况。事实上，这里研究的突变体收集已经在提供人类神经退行性疾病基因同源物spe-4（阿尔茨海默病）方面取得了丰硕的成果，表明它抑制精子发生。