Genes Assoc With Ovarian Develop /Premature Ovarian Fail

大约1-3%的女性经历了提前绝经，要么从未经历过月经初潮，要么在35岁左右就停止月经，而不是达到50岁左右的标准生育寿命。这种早发性“卵巢早衰（POF）”的一小部分是遗传的。3号染色体上的单个位点与几个家族有关。与G. Pilia博士合作，我们分离了基因FOXL2，该基因突变导致POF和眼睑畸形（构成睑袋/上睑下垂/内眦赘肉综合征，简称BPES）。我们现在正在分析FOXL2的功能，它似乎决定了卵巢卵泡的水平。我们恢复了小鼠同源基因Foxl2，并建立了敲除小鼠模型。由此产生的表型与BPES中所见的眼睑和卵巢特征相似。在基因敲除小鼠的卵巢中，发生了普遍的卵泡形成失败。完整的单个卵泡不能从原始卵母细胞巢中形成；卵巢中所有体细胞谱系的发育都被阻断；所有卵母细胞随后都能抑制生长并发生凋亡。研究结果指向了FOXL2缺乏的女性发生POF的一个可比较的整体机制。为了从分子水平上理解POF中卵泡形成和维持的失败，我们使用NIA 15K cDNA微阵列[由M. Ko博士（LG）开发]分析了小鼠正常卵巢发育。到目前为止，我们已经比较了新生小鼠卵巢中表达的基因图谱，其中卵巢卵泡刚刚开始形成，与成熟卵巢中表达的基因队列相比，卵泡已经完全形成。仅在出生时的卵泡细胞或新生或成熟小鼠的卵母细胞中表达的标记基因已被恢复用于进一步的功能研究。我们将从Foxl2敲除小鼠发育中的卵巢的表达谱开始，将这些基因与在遗传性POF中功能受到严重影响的基因子集进行比较分析。在该模型中，将通过确定Foxl2调控的靶基因来表征编程和协调基因功能的中断。

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.