Regulation of Female Meiosis by the Cdc25b Phosphatase

描述：（改编自申请人摘要）在所有脊椎动物中，卵母细胞 发育在减数分裂I（MI）的前期被阻止。卵母细胞可以保留 在生物体的整个生殖寿命中， 人类长达四十年。减数分裂的恢复需要激活 成熟促进因子（MPF）是细胞周期蛋白B和细胞周期蛋白依赖性蛋白的复合物， 激酶-1（CDK 1/p34 cdc 2）。哺乳动物MPF激活的机制 仍然难以捉摸，不能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。我们最近证明卵母细胞 缺乏MPF激活剂Cdc 25 B磷酸酶的小鼠， 减数分裂前期停滞后。缺乏Cdc 25 B的小鼠提供了第一个遗传 用于哺乳动物的前期阻滞的模型，并提供了一种独特的试剂， 剖析调节哺乳动物减数分裂的分子机制。具体 该提案的目的是为了回答有关 控制哺乳动物的减数分裂，并为未来的研究提供科学依据。 临床进展具体目标是：（一）确定 Cdc 25 B在成熟卵母细胞中的亚细胞定位，ii）为了确定Cdc 25 B在成熟卵母细胞中的亚细胞定位， iii）为了确定Cdc 25 B分子的途径是否 在有丝分裂过程中调节Cdc 25 B活性也在减数分裂过程中起作用，和iv） 利用Cdc 25 B蛋白作为一个独特的标签来解析调控细胞凋亡的途径， 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.