Grem1 and Grem2 in embryonic ovary development

Grem1 和 Grem2 在胚胎卵巢发育中的作用

• 批准号: 10584129
• 负责人: STEPHANIE A. PANGAS
• 金额: $ 32万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584129
• 关键词: Adult; Affect; Aneuploidy; Apoptosis; Architecture; Binding Proteins; Birth; Bone Morphogenetic Proteins; Cell Count; Cell Death; Cell Differentiation process; Cells; Data; Defect; Development; Disease; Embryo; Embryonic Development; Family; Feedback; Female; Fertility; General Population; Genes; Genetic; Genetic Models; Genomics; Germ Cells; Goals; Health; Imaging Techniques; Infertility; Knock-out; Knockout Mice; Laboratories; Licensing; Light; Longevity; Mammals; Mediator; Meiosis; Menopause; Microscopy; Modeling; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Mutation; National Institute of Child Health and Human Development; Oocytes; Oogenesis; Optical Coherence Tomography; Ovarian; Ovary; Paracrine Communication; Pathologic; Pathology; Pathway interactions; Perinatal mortality demographics; Phenotype; Play; Population; Primordial Follicle; Proliferating; Protein Dynamics; Proteins; Regulatory Pathway; Reporter; Reproduction; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Smad Proteins; Somatic Cell; Specific qualifier value; Sterility; Strategic Planning; Structure of primordial sex cell; Subgroup; Supporting Cell; Testing; Time; Tissues; Transforming Growth Factor beta; Transplantation; Woman; antagonist; cell type; design; egg; exhaustion; experimental study; extracellular; fetal; genetic variant; idiopathic infertility; morphogens; mutant; novel; oocyte quality; ovarian reserve; primary ovarian insufficiency; protein function; reproductive; reproductive senescence; reproductive system disorder; response; single cell sequencing; subfertility; transcriptome

PROJECT SUMMARY Normally, women undergo menopause in their early fifties due to exhaustion of the pool of oocytes called the “ovarian reserve”. Oocytes are generated in large numbers during embryonic development, but the vast majority undergo programmed cell death; the remaining oocytes become enclosed within quiescent primordial follicles that make up the ovarian reserve. Pathologic development of the ovarian reserve leads to infertility or early reproductive senescence. Furthermore, meiotic errors in oocytes cause germ cell death or result in developmental defects such as aneuploidy. The molecular signals within the embryonic ovary that determine the upper and lower limits for oocyte numbers are unknown. The long-term goal of our laboratory is to identify signaling pathways that control oogenesis and thus, female reproductive lifespan. The bone morphogenetic proteins (BMPs) are a large subgroup of the transforming growth factor beta family and have conserved roles in primordial germ cell specification and development. The BMPs are known morphogens whose activity must be strictly regulated during development or pathology and disease results. There are a number of secreted extracellular BMP-binding proteins that act as molecular sinks to negatively regulate the amount of BMP “sensed” by a signal-receiving cell. Two of these BMP antagonists, GREMLIN-1 and GREMLIN-2 have genetic variants associated with primary ovarian insufficiency (POI) in women. We tested the developmental role of Grem1 and Grem2 by generating single and double knockout mice for Grem1 and Grem2. These mice display a range of defects in embryonic ovary development including changes to oocyte number and altered meiosis. The aims of this proposal are designed to (1) determine how loss of Grem1 and/or Grem2 alters embryonic ovary development; and (2) determine which signaling pathways are dysregulated in embryonic ovaries of mutant mice that drive changes in germ cell numbers. Collectively, our studies stand to uncover fundamental mechanism that regulate embryonic ovary development and oocyte numbers, which are essential for mammalian female reproduction and reproductive lifespan.

项目摘要 通常，由于卵母细胞的耗尽，妇女在五十年代初期经历了更年期 “卵巢储备”。卵母细胞在胚胎发育过程中大量生成，但是蒸气 多数人经历了程序性细胞死亡；其余的卵母细胞被封闭在静态原始中 组成卵巢储备的卵泡。卵巢储备的病理发展导致不孕或 早期生殖感应。此外，卵母细胞中的减数分裂错误会导致生殖细胞死亡或导致 发育缺陷，例如非整倍性。确定胚胎卵巢内的分子信号 卵母细胞数的上和下限尚不清楚。我们实验室的长期目标是确定 控制卵子发生的信号通路，因此是女性生殖寿命。骨形态发生 蛋白质（BMP）是转化生长因子β家族的大型亚组，并且在 原始生殖细胞规范和发育。 BMP是已知的形态剂，其活性必须是 在发育或病理和疾病结果中严格调节。有很多分泌 充当分子下沉的细胞外BMP结合蛋白，以负调节BMP的量“感官” 通过信号接种单元。这些BMP拮抗剂中的两个，Gremlin-1和Gremlin-2具有遗传变异 与妇女的原发性卵巢不足（POI）相关。我们测试了Grem1和 GREM2通过为GREM1和GREM2生成单敲门小鼠和双基因敲除小鼠。这些小鼠显示了 胚胎卵巢发育中的缺陷，包括对卵母细胞数的变化和减数分裂的改变。目的 该建议旨在（1）确定GREM1和/或GREM2的损失如何改变胚胎卵巢 发展; （2）确定突变小鼠胚胎卵巢中哪些信号通路失调 驱动生殖细胞数的变化。总的来说，我们的研究旨在发现基本机制 调节胚房发育和卵母细胞数，这对于哺乳动物女性至关重要 繁殖和繁殖寿命。