Role of CDC14B in mouse oocyte maturation

描述（由申请人提供）：单倍体配子是有性生殖所必需的，由二倍体前体细胞通过减数分裂产生。在雌性中，卵母细胞经历2个主要的减数分裂特异性细胞周期转变，其调控机制尚不清楚。第一个过渡是减数分裂恢复，卵母细胞退出延长的前期停滞，进入第一个减数分裂M期（Ml），第二个是Ml和MIl之间的过渡，同源染色体分离，没有一轮DNA合成发生。本研究计划的总体目标是确定双特异性磷酸酶CDC14B在小鼠卵母细胞这些转变过程中的作用，并建立一个独立的研究项目，重点了解调节这些转变的错误如何与不孕症相关。本提案的具体目的是验证以下假设：1)防止减数分裂过早成熟，2)通过逆转周期蛋白依赖性激酶CDK1的作用来调节mi到mii的转变。本提案的K99部分将在宾夕法尼亚大学Richard Schultz博士的指导下进行。舒尔茨博士对卵母细胞成熟有着长期的兴趣，并指导了许多博士后，他们现在是成功的独立研究者。此外，该大学致力于培养下一代科学家。该提案还描述了候选人向独立职业过渡的详细计划，包括教学课程工作和以实时成像技术为重点的小组会议，这是候选人打算在K99阶段学习并将在R00阶段继续使用的技术。

DESCRIPTION (provided by applicant): Haploid gametes, that are essential for sexual reproduction, are generated from diploid precursor cells via meiosis. In females, oocytes undergo 2 major meiosis-specific, cell-cycle transitions whose regulation is poorly understood. The first transition is meiotic resumption where oocytes exit a prolonged prophase arrest and enter the first meiotic M phase (Ml), and the second is the transition between Ml and MIl where homologous chromosomes separate and no round of DNA synthesis occurs. The overall goal of this research proposal is to determine the role of the dual-specificity phosphatase CDC14B during these transitions in mouse oocytes with a long-term goal of establishing an independent research program that focuses on understanding how errors in regulating these transitions are linked to infertility. The specific aims of this proposal are to test the hypotheses that CDC14B is required to 1) prevent premature meiotic maturation and to 2) regulate the MI-to-MII transition through reversing the actions of the cyclin-dependent kinase, CDK1. The K99 portion of this proposal will be conducted under the mentorship of Dr. Richard Schultz at the University of Pennsylvania. Dr. Schultz has a long-standing interest in oocyte maturation and has mentored many postdoctoral fellows who are now successful independent investigators. Furthermore, the university is committed to training the next generation of scientists. This proposal also describes a detailed plan for the candidate's transition to an independent career including didactic course work and group meetings with a focus on live imaging techniques, a technology the candidate intends on learning in the K99 phase and will continue to use during the R00 phase. PUBLIC RELEVANCE: Meiosis is the process that generates eggs and sperm required for sexual reproduction. Female meiosis is highly error-prone in humans; ~20% of all eggs contain abnormal chromosome numbers that are linked to spontaneous abortions, stillbirths and developmental diseases like Downs Syndrome. The major goal of this proposal is to determine the role for the CDC14B phosphatase during meiosis in females using the mouse model