Control of Meiosis and Germline Proliferation

减数分裂和种系增殖的控制

• 批准号: 8299032
• 负责人: David Irwin Greenstein
• 金额: $ 30.82万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299032
• 关键词: Actomyosin; Acute; Adenylate Cyclase; Affect; Aging; Biological Models; Caenorhabditis elegans; Cell Cycle Regulation; Cells; Chimeric Proteins; Chromosomes; Communication; Congenital Abnormality; Cytoplasmic streaming; DNA Sequence Rearrangement; Data; Defect; Development; Down Syndrome; Drosophila genus; Dyes; Employee Strikes; Endocytosis; Eph Family Receptors; Event; Female; Fertility; Fertilization; Fluorescent Antibody Technique; Funding; Gap Junctions; Genes; Genetic; Genetic Models; Genetic Screening; Germ Lines; Gonadal structure; Growth; Health; Hormones; Human; Individual; Injection of therapeutic agent; Label; Learning; Link; Mammals; Maternal Age; Mediating; Meiosis; Metaphase; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Analysis; Molecular Genetics; Mutation; Nematoda; Nuclear Envelope; Oocytes; Oogenesis; Organism; Ovarian; Physiological; Play; Property; Proteins; RNA Interference Pathway; Regulation; Reproduction; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Somatic Cell; Spontaneous abortion; System; Testing; Work; abstracting; age effect; base; egg; genetic analysis; hormone regulation; insight; intercellular communication; neuronal cell body; notch protein; oocyte maturation; public health relevance; research study; response; sperm cell; sperm protein; trafficking

DESCRIPTION (provided by applicant): Abstract Sexual reproduction of multicellular organisms depends critically on communication between cells of the somatic gonad and the germ line, and ultimately between sperm and egg. In many species, intercellular signaling plays a pivotal role in coordinating meiosis and fertilization: developing oocytes arrest at diakinesis for prolonged periods and resume meiosis (meiotic maturation) in response to hormones. Meiotic maturation is defined by the transition between diakinesis and metaphase of meiosis I and is accompanied by nuclear envelope breakdown, cortical cytoskeletal rearrangement, and meiotic spindle assembly. There is an acute need for information on how intercellular signals control meiotic progression because chromosome missegregation in female meiosis I is the leading cause of Down syndrome and miscarriage. The nematode Caenorhabditis elegans has emerged as a paradigm for studying meiosis and germline proliferation and their regulation by conserved signaling pathways. Our studies demonstrate that C. elegans sperm export the major sperm protein (MSP) to trigger oocyte MAP kinase activation and meiotic maturation. In the prior funding period, we discovered that somatic G1s and G1o/i signaling pathways function in parallel with the MSP/Eph receptor to regulate meiotic maturation. Our genetic data implicate gap-junctional communication between oocytes and somatic cells of the gonad as a critical target of MSP signaling. Genetic analysis also uncovered a broader role for sperm signals and gap-junctional communication in regulating the actomyosin-dependent cytoplasmic streaming that drives oocyte growth. Soma-germline interactions play many essential roles during reproduction, yet much remains to be learned about their underlying mechanistic basis, hence we will: 1) Define the molecular composition of sheath/oocyte gap junctions; 2) Test the hypothesis that MSP signaling targets inhibitory sheath/oocyte gap junctions to promote meiotic maturation; and 3) Analyze roles for MSP signaling, gap-junctional communication, and Notch signaling in coordinating oocyte growth and meiotic maturation. These studies will define the normal signaling mechanisms controlling late events in oogenesis and provide insights into how they may go awry when signaling is perturbed. Since intercellular signaling and cell cycle control mechanisms are evolutionarily conserved, studies in genetic model systems will provide crucial information on the underlying causes of meiotic errors in humans. PUBLIC HEALTH RELEVANCE: Prior work has established a link between the origin of meiotic errors in oocytes and aberrant regulation of hormonal signaling in the aging ovarian microenvironment. This maternal-age effect represents the major barrier to human fertility and is the chief cause of human birth defects. Because of the extensive evolutionary conservation of developmental mechanisms, these studies in C. elegans will define the signaling mechanisms controlling late events in oogenesis and provide insights into how they may go awry when signaling is perturbed.

描述（由申请人提供）：多细胞生物的抽象有性繁殖取决于体细胞性腺和细菌细胞之间的通信，最终在精子和鸡蛋之间。在许多物种中，细胞间信号传导在协调减数分裂和受精方面起着关键作用：长期在抑郁症中释放卵母细胞停滞，并恢复减数分裂（减数分裂成熟）响应激素。减数分裂成熟是由减数分裂I和中期I之间的过渡来定义的，并伴随着核包膜分解，皮质细胞骨骼重排和减数分裂纺锤体组件。关于细胞间信号如何控制减数分裂进程的急需信息，因为女性减数分裂中的染色体错误分析I是唐氏综合症和流产的主要原因。线虫秀丽隐杆线虫已成为研究减数分裂和种系增殖及其通过保守信号通路的调节的范式。我们的研究表明，秀丽隐杆线虫精子导出主要的精子蛋白（MSP）触发卵母细胞MAP激酶激活和减数分裂成熟。在以前的资金期间，我们发现体细胞G1和G1O/I信号通路与MSP/EPH受体并行起作用以调节减数分裂成熟。我们的遗传数据暗示卵母细胞和性腺的体细胞之间的间隙 - 界面通信是MSP信号传导的关键靶标。遗传分析还发现了精子信号和间隙 - 连通性在调节依赖肌动蛋白依赖性细胞质流的广泛作用，从而驱动卵母细胞生长。 Soma-Germline相互作用在繁殖过程中起着许多基本作用，但有关其基本机理基础还有很多待了解，因此我们将：1）定义护套/卵母细胞间隙连接的分子组成； 2）检验以下假设：MSP信号靶向抑制鞘/卵母细胞间隙连接以促进减数分裂成熟； 3）分析MSP信号传导，间隙 - 功率通信以及缺口信号传导在卵母细胞生长和减数分裂成熟中的作用。这些研究将定义控制卵子发生后期事件的正常信号传导机制，并提供有关信号传导在扰动时如何出现问题的见解。由于细胞间信号传导和细胞周期控制机制在进化上是保守的，因此在遗传模型系统中的研究将提供有关人类减数分裂误差的根本原因的关键信息。公共卫生相关性：先前的工作已经建立了卵母细胞中减数分裂错误的起源与衰老卵巢微环境中激素信号传导异常调节之间的联系。这种母亲时代的作用代表了人类生育能力的主要障碍，是人类出生缺陷的主要原因。由于对发育机制的广泛进化保护，秀丽隐杆线虫中的这些研究将定义控制卵子发生后期事件的信号传导机制，并提供有关在信号扰动时如何出现问题的见解。