Molecular factors of female high-fertility - a study of two outbred mouse lines selected for increased female reproductive performance

高生育率的因素只是描述得很差。大多数具有生殖表型的转基因或基因敲除模型是低育或不育的。只有少数基因型与提高生育力（0.2%）或增加产仔数（1%）有关。因此，我们缺乏高生育率模式。在这项研究中，我们通过使用两种全球独特的小鼠模型生育系（FL）1和FL 2来改变观点。与无生长迟缓迹象的对照组（Ctrl）相比，这些小鼠的同窝仔数量以及每窝总出生体重几乎增加了一倍。本项目的目的是从表型到基因型的改变来平行表征这些选择系。先驱研究表明，两种FL都能排卵更多的卵母细胞。因此，我们假设（i）卵泡池的大小发生了变化（卵泡池升高模型）或（ii）由于选择过程中下丘脑-垂体-性腺轴（HPG轴）的激素变化，排卵卵泡的数量增加（超排卵样模型）。这两种假设将在不同的卵巢发育阶段进行测试，确定卵泡池的大小，并分析HPG轴的内分泌变化。目前还不清楚排卵卵巢在180多代后保持其特征的程度。同时比较FLs和Ctrl line将为高育性表型组的复杂性和多样性提供新的信息。整体基因表达方法将绘制一幅关于表型如何被保证的全局图。这些网络将与已经存在的数据进行比较，基于QTL分析，以产生一个潜在的候选基因或基因标记的增加fertility.Brilliant甲酚蓝（BCB）超活力染色确定葡萄糖-6-磷酸脱氢酶（G6 PDH）的活性，是卵母细胞成熟和发育能力的标志。初步实验表明，FL 1和FL 2小鼠从有腔卵泡分离的卵母细胞中G6 PDH活性降低。我们将使用IVF实验来测试这些差异是否是生育能力提高的促成因素。除了这些功能的研究，我们将分析所有三个小鼠系的卵母细胞蛋白质组的依赖于他们的BCB状态的下游影响降低G6 DPH activity.By分析两个FL在平行从表型的基因型，我们期望新的基本见解卵巢的生理适应和受影响的基因和生物特征的生育能力增加。此外，我们推测，这些基因和途径的调节，以保持高生育力也是重要的表型降低生育力。因此，我们认为这项工作的基础上，进一步调查，研究高生育力的表型，基因敲除/-在和其他物种的多育性标记的名单将测试。

Factors of high-fertility are just poorly described. The majority of transgenic or knockout models with a reproductive phenotype is subfertile or sterile. Only a minority of genotypes is linked with enhanced fertility (0.2%) or increased litter size (1%). Thus, we are lacking of high-fertility models. In this study we change the perspective by using two worldwide unique mouse models fertility line (FL) 1 and FL2 selected for high-fertility. These mice almost doubled the number of littermates as well as the total birth weight per litter in comparison to an unselected control line (Ctrl) with no signs of growth retardation in the offspring. The aim of this project is to characterize these selection lines in parallel from phenotypic to genotypic alterations. Pioneer studies reveal both FLs ovulate more oocytes. Hence, we hypothesize that (i) the size of the follicle pool has changed (elevated follicle pool model) or (ii) the amount of ovulated follicles increased due to hormonal alterations in the hypothalamic-pituitary-gonad axis (HPG axis) during selection process (superovulation like model). Both hypotheses will be tested on different ovarian developmental stages determining the follicle pool size and in addition analysing for endocrine alteration of the HPG axis.Currently it is unknown how high ovulating ovaries are maintained their characteristics after more than 180 generations. Comparing both FLs and Ctrl line in parallel will provide new information of the complexity and diversity of the phenome high-fertility. The holistic gene expression approach will draw a global picture of how the phenotype is warranted. These networks will be compared with already existing data based on QTL analysis to generate a list of potential candidate genes or gene markers of increased fertility.Brilliant cresyl blue (BCB) supravital staining determines the activity of glucose-6-phosphate dehydrogenase (G6PDH) and is a marker of oocyte maturation and developmental competence. Pilot experiments reveal FL1 and FL2 mice have decreased activity of G6PDH in oocytes isolated from antral follicles. We will test if these differences are contributing factors of increased fertility using IVF experiments. In addition to these functional studies we will analyse the oocyte proteome of all three mouse lines in dependence of their BCB-status for downstream effects of decreased G6DPH activity.By analysing both FLs in parallel from the phenotype to the genotype we expect new basic insights into physiological adaptations of the ovary and affected genes and biosignatures of increased fertility. In addition we hypothesize that those genes and pathways regulated to maintain high fertility are also of importance to the phenotype reduced fertility. Hence we consider the work as a basis for further investigations to study the phenotype of high-fertility using gene knockout/-in and will test the list of prolificacy markers in other species.