Regulation of meiotic arrest by a Gs-linked receptor

描述(申请人提供)：哺乳动物卵泡是细胞如何交流来调节复杂组织内细胞周期的一个引人注目的例子。特别是，包围卵母细胞的体细胞向卵母细胞发出信号，维持减数分裂前期停滞，然后作为对黄体生成素(LH)的响应，这些相同的体细胞发出相反的信号，导致减数分裂恢复。该实验室最近的工作表明，维持前期停滞需要Gs家族的异源三聚体G蛋白和Gs连接的受体GPR3的活性，这两种受体都位于卵母细胞中。这项拟议的研究将探讨GPR3在维持前期停滞以及重新启动减数分裂细胞周期中的作用。目的一是检测Gpr3在卵子发生过程中的表达，进一步确定Gpr3基因敲除小鼠的表型，并确定维持减数分裂停滞所需的Gpr3是否完全源于卵母细胞中的Gpr3。目的二是探讨体细胞的存在是否以及如何将卵泡封闭的卵母细胞中Gs和GPR3的活性维持在高于分离卵母细胞的水平。目的三是研究在黄体生成素诱导的减数分裂重新启动过程中，来自体细胞的信号是否以及如何降低Gs和GPR3的活性。这些研究将为G蛋白连接受体在细胞-细胞信号和细胞周期调节中的功能提供重要的新见解。最终，这种关于正常细胞周期调控的知识可能适用于细胞周期失去控制的病理条件的治疗。

DESCRIPTION (provided by applicant): The mammalian ovarian follicle presents a remarkable example of how cells communicate to regulate the cell cycle within a complex tissue. In particular, the somatic cells that surround the oocyte send a signal to the oocyte that maintains meiotic prophase arrest, and then in response to luteinizing hormone (LH), these same somatic cells send an opposite signal, causing meiosis to resume. Recent work from this laboratory has shown that the maintenance of prophase arrest requires the activity of a heterotrimeric G protein of the Gs family, and a Gs-linked receptor, GPR3, both located in the oocyte. The proposed studies will investigate the function of GPR3 in maintaining prophase arrest, as well as in restarting the meiotic cell cycle. Aim one is to examine the expression of Gpr3 during oogenesis, to further characterize the phenotype of a Gpr3 knockout mouse, and to determine whether the Gpr3 requirement for the maintenance of meiotic arrest is due entirely to GPR3 in the oocyte. Aim two is to investigate whether and how the presence of the somatic cells maintains the activities of Gs and GPR3 in follicle-enclosed oocytes at levels greater than those in isolated oocytes. Aim three is to investigate whether and how signals from the somatic cells decrease the activities of Gs and GPR3 during LH-induced reinitiation of meiosis. These studies will provide important new insights into the function of G-protein linked receptors in cell-cell signaling and cell cycle regulation. Ultimately, this knowledge concerning the regulation of the normal cell cycle may be applicable to treatment of pathological conditions in which cell cycle control is lost.