Regulation of Female Meiosis by the Cdc25b Phosphatase

描述：(改编自申请人的摘要)在所有脊椎动物中，卵母细胞 发育受阻于减数分裂I(MI)的前期。卵母细胞可以保留 在生物体的整个生殖寿命内在这种状态下被逮捕；在 人类长达四十年之久。恢复减数分裂需要激活 成熟促进因子(MPF)--细胞周期蛋白B和细胞周期蛋白依赖性复合体 激酶-1(CDK1/p34cdc2)。哺乳动物MPF激活的机制有 仍然难以捉摸，无法使人类卵母细胞成熟是一个主要问题 用于体外受精(IVF)诊所。我们最近证明了卵母细胞 缺乏MPF激活剂的小鼠，CDC25B磷酸酶不能恢复 前期停滞后的减数分裂。缺乏CDC25B的小鼠提供了第一个基因 哺乳动物早期停滞的模型，并提供了一种独特的试剂 剖析调控哺乳动物减数分裂的分子机制。具体的 该提案的目的是回答有关 哺乳动物减数分裂的调控为今后的研究提供科学依据 临床进展。具体目标是：i)确定 CDC25B在成熟卵母细胞中的亚细胞定位，II)确定 CDC25B分子的功能结构域，III)确定途径 在有丝分裂过程中调节CDC25B活性的物质也在减数分裂过程中起作用，以及iv) 利用CDC25B蛋白作为唯一的标记来剖析调控途径 哺乳动物的前期停滞和减数分裂恢复。

DESCRIPTION: (Adapted from the applicant's abstract) In all vertebrates, oocyte development is arrested at the prophase of meiosis I (MI). Oocytes can remain arrested in this state for the entire reproductive lifespan of the organism; in humans as long as forty years. Resumption of meiosis requires activation of maturation promoting factor (MPF), the complex of cyclin B and cyclin dependent kinase-1 (CDK1/p34cdc2). The mechanism of MPF activation in mammals has remained elusive and the inability to mature human oocytes is a major problem for in vitro fertilization (IVF) clinics. We recently demonstrated that oocytes from mice lacking an MPF activator, the Cdc25B phosphatase, fail to resume meiosis after prophase arrest. Mice lacking Cdc25B provide the first genetic model for prophase arrest in mammals and provide a unique reagent with which to dissect the molecular mechanisms regulating mammalian meiosis. The specific aims of the proposal are designed to answer fundamental questions about the control of meiosis in mammals and provide the scientific foundation for future clinical advances. The specific aims are designed: i) To determine the subcellular localization of Cdc25B in the maturing oocyte, ii) To define the functional domains of the Cdc25B molecule, iii) To determine whether pathways that regulate Cdc25B activity during mitosis also act during meiosis, and iv) To use the Cdc25B protein as a unique tag to dissect the pathway controlling prophase arrest and meiotic resumption in mammals.