New Mouse Mutation Exhibiting Failed Fertilization

描述（由申请人提供）：在世界范围内，夫妇希望管理自己的生殖，因此非常需要更多样化的避孕药具，特别是针对男性生殖方面的避孕药具。了解男性不育的原因可能有助于确定合适的避孕目标。在杰克逊实验室，生殖基因组学项目使用全基因组ENU （n -乙基-n -亚硝基脲）诱变来诱导小鼠基因组的随机突变，并筛选显示不育的突变体。在这个程序中发现的一个新突变，ferf1（受精失败1），是本提案的主题。受影响的男性在许多参数（体重、性行为、精子数量和形态）方面是正常的。该突变的表型为育种失败。此外，在体外受精过程中，受影响雄性的精子表现出异常凝集，无法与透明带封闭的卵母细胞受精，尽管它们能够受精并激活无带的卵母细胞。了解由铁f1基因编码的蛋白质可以深入了解精子获能和受精的鲜为人知的步骤，并可能确定一种新的避孕靶点。受铁f1突变影响的蛋白质可能是生殖细胞中合成的蛋白质。或者，它可以从体细胞分泌，也许是附睾，并包裹在精子上，从而影响它们的能力和受精的成功。Aim 1的目的是确定铁精子从附睾释放到与卵泡透明带相互作用后的表型特征，并通过附睾液体转换实验确定铁精子的异常凝集特征和受精表型是精子固有的还是男性生殖道分泌物固有的。Aim 2的目标是创建围绕铁f1基因的高分辨率遗传图谱，并最终定位克隆和识别被铁f1突变中断的基因。铁f1突变的表型影响受精的重要步骤，可以为男性不育提供见解，甚至可能确定一个有前途的避孕靶点。因此，在相对较短的资助期内进行迅速和集中的攻击是可取的，以便使项目达到为该概念的未来研究和发展设定优先级的程度。

DESCRIPTION (provided by applicant): Worldwide, couples want to manage their own reproduction and there is great need for more diverse contraceptives, especially ones targeted to aspects of male reproduction. Understanding causes of male infertility will likely aid in identification of suitable contraceptive targets. At The Jackson Laboratory, the ReproGenomics Program uses whole-genome ENU [N-ethyl-N-nitrosourea] mutagenesis to induce random mutations in the mouse genome and screens for mutants exhibiting infertility. A new mutation identified in this program, ferf1 (fertilization failure 1), is the subject of this proposal. Affected males are normal with respect to many parameters (body weight, sexual behavior, sperm count and morphology). The phenotype of the ferf1 mutation is breeding failure. Furthermore, during fertilization in vitro, sperm from affected males show abnormal agglutination and fail to fertilize zona pellucida-enclosed oocytes, although they do fertilize and activate zona-free oocytes. Knowledge of the protein encoded by the ferf1 gene could yield insight into poorly understood steps in sperm capacitation and fertilization and possibly identify a novel contraceptive target. The protein affected by the ferf1 mutation could be one synthesized in the germ cells. Alternatively, it could be secreted from somatic cells, perhaps the epididymis, and coat the sperm, thereby affecting their ability to become capacitated and their success in fertilization. The goals in Aim 1 are to determine the phenotypic characteristics of ferf1 sperm after their release from the epididymis to their interaction with the acolyte's zona pellucida and to determine, by epididymal fluid switching experiments, if the abnormal agglutination characteristics and fertilization phenotype of ferf1 sperm are inherent to the sperm or to male reproductive tract secretions. The goal of Aim 2 is to create a high-resolution genetic map surrounding the ferf1 gene and, ultimately, to positionally clone and identify the gene interrupted by the ferf1 mutation. The phenotype of the ferf1 mutation impacts important steps in fertilization, could provide insight into male infertility, and may even identify a promising contraceptive target. Thus, an expeditious and focused attack over a relatively short funding period is desirable to bring the project to the point of setting priorities for future research and development of the concept.