Genes Assoc With Ovarian Develop /Premature Ovarian Fail

与卵巢发育/卵巢早衰相关的基因

• 批准号: 6969324
• 负责人: Ramaiah Nagaraja
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6969324
• 关键词: aging; chromosome translocation; corpus luteum; developmental genetics; embryogenesis; eyelid disorder; family genetics; female; gene deletion mutation; gene expression; gene expression profiling; genetic mapping; genetic markers; genetically modified animals; graafian follicles; laboratory mouse; mammalian embryology; menopause; microarray technology; nucleic acid sequence; ovary; ovary disorder; sex chromosomes

About 1-3% of all women undergo precocious menopause, either never going through menarche or stopping menstruation by the mid-30's, rather than reaching the standard reproductive lifespan of about 50. A fraction of such instances of early-onset "premature ovarian failure (POF)" is genetic. A single locus on chromosome 3 is implicated in several families. In collaboration with the group of Dr. G. Pilia, we isolated the gene, FOXL2, in which mutations cause POF and an eyelid malformation (constituting the syndrome Blepharophimosis/Ptosis/Epicanthus Inversus, or BPES). We are now analyzing the function of FOXL2, which appears to determine the level of ovarian follicles. We recovered the mouse orthologue, Foxl2, and generated a knockout mouse model. The resulting phenotype mimics eyelid and ovarian features seen in BPES. In the ovaries of the knockout mice, pervasive failure of follicle formation occurs. Complete individual follicles never form from primitive oocyte nests; development of all somatic lineages in the ovary is blocked; and all oocytes can subsequently be derepressed for growth and undergo apoptosis. The results point toward a comparable overall mechanism for POF in women deficient in FOXL2. To help understand the failure of follicle formation and maintenance in POF at a molecular level, we have analyzed normal ovarian development in mice using the NIA 15K cDNA microarray [developed by the group of Dr. M. Ko (LG)]. We have thus far compared the profile of genes expressed in ovaries of newborn mice, in which ovarian follicles are just starting to form, to the cohort of genes expressed in mature ovary, in which follicles are fully formed. Marker genes expressed in follicle cells only at birth, or in oocytes of nascent or in mature mice, have been recovered for further functional studies. These will be analyzed in comparison to the subset of genes whose function is sharply affected in hereditary POF, starting with the expression profiling of developing ovaries from Foxl2 knockout mice. In that model, the interruption of programmed and coordinated gene function will be characterized by determining the target genes regulated by Foxl2.

大约1-3%的女性经历过早的更年期，要么从未经历过初潮，要么在30年代中期停止月经，而不是达到约50岁的标准生殖寿命。一小部分早发性卵巢早衰（POF）是遗传性的。3号染色体上的一个基因座与几个家族有关。与G博士的团队合作。我们分离出FOXL 2基因，该基因突变导致POF和眼睑畸形（构成睑裂狭小综合征/上睑下垂/内眦赘皮，或BPES）。我们现在正在分析FOXL 2的功能，它似乎决定了卵泡的水平。我们回收了小鼠直系同源物Foxl 2，并产生了敲除小鼠模型。由此产生的表型模拟了BPES中观察到的眼睑和卵巢特征。在基因敲除小鼠的卵巢中，卵泡形成普遍失败。完整的单个卵泡从未从原始卵母细胞巢形成;卵巢中所有体细胞谱系的发育被阻断;并且所有卵母细胞随后可以被去抑制以生长并经历凋亡。结果表明FOXL 2缺陷妇女POF的总体机制相当。为了从分子水平上帮助理解卵巢早衰中卵泡形成和维持的失败，我们使用NIA 15 K cDNA微阵列分析了小鼠正常卵巢发育。Ko（LG）]。到目前为止，我们已经比较了新生小鼠卵巢中表达的基因谱，其中卵泡刚刚开始形成，成熟卵巢中表达的基因队列，其中卵泡完全形成。标记基因表达的卵泡细胞只在出生时，或在卵母细胞的新生或成熟的小鼠，已恢复进一步的功能研究。这些将被分析比较的基因的子集，其功能是急剧影响遗传性POF，从Foxl 2基因敲除小鼠的卵巢发育的表达谱开始。在该模型中，程序化和协调的基因功能的中断将通过确定由Foxl 2调节的靶基因来表征。