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， 睾丸胚胎干细胞及转基因技术的研究进展 鼠标技术使研究人员能够解决基本的 这些因素中的一些在体内的功能。了解卵巢 功能，我们已经建立了重要的转基因小鼠模型， 生长分化因子9（GDF-9），促卵泡激素 (FSH)、激活素受体II（ActRII）和生殖细胞核因子 （GCNF）。缺乏GDF-9、FSH和ActRII的雌性小鼠由于 在卵泡形成的特定阶段。相比之下，GCNF- 由于GCNF在妊娠中期的重要作用，缺陷小鼠在妊娠中期死亡。 胎盘的胚外发育。GCNF是孤儿成员， 核受体超家族在发育中的生殖细胞中表达， 成年老鼠在卵母细胞中，GCNF从一层表达 通过排卵的初级卵泡阶段类似于TGF-β家族 GDF-9成员。此外，我们最近发现了另一种TGF-β 家族成员Novel 1，其具有卵母细胞特异性表达模式 类似于GDF-9和GCNF。描述GCNF和Novel的功能 1在卵巢发育过程中，我们将产生几个新的转基因 鼠标线。这些研究的具体目的如下：1） 表征Novel 1在小鼠卵巢发育中的作用; 2）研究 GCNF在卵母细胞成熟过程中的生理功能; 3）分析GCNF在卵母细胞成熟过程中的作用。 GCNF和Novel 1在小鼠和人卵母细胞和生殖细胞中的调节 4）使用具有多重缺陷和mRNA的转基因小鼠 表达分析以确定几个基因的相互作用 卵巢的发育和功能。 上述研究将评估这些基因的重要作用 在卵巢发育中。我们假设Novel 1缺陷小鼠和 卵巢特异性敲除GCNF的小鼠将继发不育 卵泡发育的早期阻滞。如果这个假设成立， 突变雌性小鼠表现出生育缺陷，GCNF和Novel 1可能是 新避孕药的潜在靶点和人类 不孕

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.