Grem1 and Grem2 in embryonic ovary development

项目总结 正常情况下，女性在50岁出头时会因卵母细胞池耗尽而绝经。 “卵巢储备”。卵母细胞在胚胎发育过程中大量产生，但大量的 大多数人经历程序性细胞死亡；剩余的卵母细胞被包裹在静止的原始细胞中 组成卵巢储备的卵泡。卵巢储备的病理发育导致不孕不育或 早期生殖衰老。此外，卵母细胞的减数分裂错误会导致生殖细胞死亡或导致 发育缺陷，如非整倍体。胚胎卵巢内的分子信号决定了 卵母细胞数量的上限和下限尚不清楚。我们实验室的长期目标是确定 控制卵子发生从而控制雌性生殖寿命的信号通路。骨形态发生学 蛋白质(BMP)是转化生长因子β家族的一个大亚类，在 原始生殖细胞规范和发育。BMP是已知的形态生物质，其活性必须是 在发育或病理和疾病结果期间严格监管。有一些秘密的 细胞外骨形成蛋白结合蛋白作为分子汇负性调节骨形态发生蛋白的“感知”量 通过信号接收单元。其中两种BMP拮抗剂gremlin-1和gremlin-2具有遗传变异 与女性原发性卵巢功能不全(POI)相关。我们测试了Grem1和Grem1的发育作用 通过为Grem1和Grem2产生单基因敲除和双基因敲除小鼠。这些鼠标显示了一系列 胚胎卵巢发育的缺陷，包括卵母细胞数量的改变和减数分裂的改变。的目标是 这项建议旨在(1)确定Grem1和/或Grem2的缺失如何改变胚胎卵巢 以及(2)确定哪些信号通路在突变小鼠的胚胎卵巢中失调 这会导致生殖细胞数量的变化。总体而言，我们的研究将揭示 调节胚胎卵巢发育和卵母细胞数量，这对哺乳动物雌性来说是必不可少的 生殖和生殖寿命。

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.