Control of Meiosis and Germline Proliferation

减数分裂和种系增殖的控制

• 批准号: 7858286
• 负责人: David Irwin Greenstein
• 金额: $ 31.21万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7858286
• 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; 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）：摘要多细胞生物的有性生殖关键取决于体细胞性腺和生殖细胞之间的通讯，并最终取决于精子和卵子之间的通讯。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发挥着关键作用：发育中的卵母细胞在终变过程中长时间停滞，并响应激素而恢复减数分裂（减数分裂成熟）。减数分裂成熟是由减数分裂 I 的终变期和中期之间的过渡定义的，并伴随着核膜破裂、皮质细胞骨架重排和减数分裂纺锤体组装。由于女性减数分裂 I 中的染色体错误分离是唐氏综合症和流产的主要原因，因此迫切需要有关细胞间信号如何控制减数分裂进展的信息。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调节的范例。我们的研究表明，线虫精子输出主要精子蛋白（MSP）来触发卵母细胞 MAP 激酶激活和减数分裂成熟。在之前的资助期间，我们发现体细胞 G1s 和 G1o/i 信号通路与 MSP/Eph 受体平行发挥作用，调节减数分裂成熟。我们的遗传数据表明卵母细胞和性腺体细胞之间的间隙连接通讯是 MSP 信号传导的关键目标。遗传分析还揭示了精子信号和间隙连接通讯在调节驱动卵母细胞生长的肌动球蛋白依赖性细胞质流中的更广泛作用。体细胞-种系相互作用在生殖过程中发挥着许多重要作用，但其潜在的机制基础还有很多需要了解，因此我们将：1）定义鞘/卵母细胞间隙连接的分子组成； 2) 检验 MSP 信号传导靶向抑制鞘/卵母细胞间隙连接以促进减数分裂成熟的假设； 3) 分析 MSP 信号、间隙连接通讯和 Notch 信号在协调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晚期事件的正常信号传导机制，并深入了解当信号传导受到干扰时它们如何可能出错。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，因此遗传模型系统的研究将为人类减数分裂错误的根本原因提供重要信息。公共健康相关性：先前的工作已经确定了卵母细胞减数分裂错误的起源与衰老卵巢微环境中激素信号传导的异常调节之间的联系。这种母亲年龄效应是人类生育能力的主要障碍，也是人类出生缺陷的主要原因。由于发育机制的广泛进化保守性，这些对秀丽隐杆线虫的研究将定义控制卵子发生晚期事件的信号传导机制，并深入了解当信号传导受到干扰时它们如何可能出错。