TRANSGENIC MOUSE MODELS TO STUDY OVARIAN FUNCTION

哺乳动物的繁殖是一个复杂的过程，需要 下丘脑、垂体和卵巢水平的多种因素和 睾丸。胚胎干细胞及其转基因研究进展 鼠标技术使调查人员能够解决关键问题 这些因子中的几个在体内的作用。了解卵巢 功能，我们创造了重要的转基因小鼠模型 生长分化因子9(GDF-9)、卵泡刺激素 卵泡刺激素(FSH)、激活素受体II型(ActRII)和生殖细胞核因子 (GCNF)。缺乏GDF-9、FSH和ActRII的雌性小鼠由于 对处于卵泡发育特定阶段的黑人来说。相比之下，GCNF- 缺陷小鼠因GCNF在妊娠中期的重要作用而死亡 胎盘的胚胎外发育。GCNF是以下组织的孤儿成员 核受体超家族在发育中的生殖细胞中的表达 成年老鼠。在卵母细胞中，GCNF从一层开始表达 初级卵泡期通过排卵类似于转化生长因子-β家族 成员，GDF-9。此外，我们最近还发现了另一种转化生长因子-β 家族成员，小说1，具有卵母细胞特异性表达模式 类似于GDF-9和GCNF。GCNF和NOVICE的功能特征 在卵巢发育期间，我们将产生几个新的转基因 老鼠线。这些研究的具体目的如下：1) 鉴定新基因1在小鼠卵巢发育中的作用；2)研究 GCNF在卵母细胞成熟中的生理作用；3)分析 小鼠和人卵母细胞和生殖细胞中GCNF和新型1基因的调控 肿瘤；以及4)使用具有多个缺陷和mRNA的转基因小鼠 用表达分析来确定几个基因的相互作用 产品涉及卵巢发育和功能。 上述研究将评估这些基因的重要作用。 在卵巢发育过程中。我们假设新的1基因缺陷小鼠 具有卵巢特异性GCNF基因敲除的小鼠将是继发性不孕 到卵泡发生的早期障碍。如果这一假设是真的，那么这些 突变的雌性小鼠表现出生育缺陷，GCNF和新的1可能是 新型避孕药的潜在靶点和人类的治疗 不孕不育。

Mammalian reproduction is a complex process requiring the interaction of multiple factors at the levels of hypothalamus, pituitary, and ovaries and testes. The rapid advances in embryonic stem (ES) cell and transgenic mouse technology have allowed investigators to address the essential functions of several of these factors in vivo. To understand ovarian function, we have created important transgenic mouse models deficient in growth differentiation factor 9 (GDF-9), follicle stimulating hormone (FSH), activin receptor type II (ActRII), and germ cell nuclear factor (GCNF). Female mice deficient in GDF-9, FSH, and ActRII are infertile due to blacks at specific stages of folliculogenesis. In contrast, GCNF- deficient mice die at mid-gestation due to important role of GCNF during extraembryonic development of the placenta. GCNF is an orphan member of the nuclear receptor superfamily expressed in the developing germ cells of the adult mouse. In the oocyte, GCNF is expressed from the one layer primary follicle stage through ovulation similar to the TGF-beta family member, GDF-9. In addition, we have recently identified another TGF-beta family member, Novel 1, which has a pattern of oocyte-specific expression similar to GDF-9 and GCNF. To characterize the functions of GCNF and Novel 1 during ovarian development, we will generate several new transgenic mouse lines. The Specific Aims of these studies are as follows: 1) Characterize the role of Novel 1 in mouse ovarian development; 2) Study the physiological function of GCNF in oocyte maturation; 3) Analyze the regulation of GCNF and Novel 1 in mouse and human oocytes and germ cell tumors; and 4) Use transgenic mice with multiple defects and mRNA expression analysis to define the interrelated roles of several gene products in ovarian development and function. The above-mentioned studies will assess the important roles of these genes in ovarian development. We hypothesize that Novel 1-deficient mice and mice with an ovary-specific knockout of GCNF will be infertile secondary to early blocks in folliculogenesis. If this hypothesis is true and these mutant female mice exhibit fertility defects, GCNF and Novel 1 may be potential targets for new contraceptive agents and treatment of human infertility.