Asymmetric Meiotic Cell Division of Mammalian Oocytes

这个项目的目标是了解哺乳动物有机体是如何启动其多细胞的 在减数分裂中完成第一次不对称细胞分裂(ACD)的发育 卵母细胞的成熟和受精。减数分裂ACD不仅对成功至关重要 受精和充分发育的受精卵，也提供了独特而迷人的 对自组织机制的洞察，自组织是生物最基本的特性 系统。我们实验室和其他实验室最近使用小鼠卵母细胞作为模型系统的研究 开始解开染色体和肌动蛋白之间动态和双向的相互作用 细胞骨架在为ACD和未来胚胎建立卵母细胞极性中的作用 发展。在拟议的研究中，我们计划在这些令人兴奋的最新发现的基础上 回答三个机械问题：1)肌动蛋白动力学如何驱动卵母细胞对称性破坏 (Aim1)；2)核基因组如何直接发出细胞形态重组的信号 水平(AIM2)；以及3)一种不寻常的动力产生机制如何形成一个大细胞 (卵母细胞)，并可能影响细胞器分离和早期胚胎发育 (目标3)。为了回答这些问题，我们将采用高度创新的方法，需要完整的 分子遗传学方法与前沿成像技术、生物物理工具的结合 和数学分析。因为临床证据表明，极化的缺陷 成熟卵母细胞的组织与衰老相关的不孕症有关，我们的研究不仅有 新的智力贡献在理解细胞自组织方面的潜力 系统，但也可以为未来开发有助于改进的新方法提供基础 人类生育能力和预防出生缺陷。

The goal of this project is to understand how a mammalian organism initiates its multicellular development by completing its very first asymmetric cell divisions (ACD) - during meiotic maturation and fertilization of the oocyte. Meiotic ACD not only is critically important for successful fertilization and full developmental potential of the zygote, but also offers unique and fascinating insights into the mechanism of self-organization, a most fundamental property of biological systems. Recent studies from our lab and others using mouse oocytes as the model system have begun to unravel dynamic and bi-directional interplays between the chromosomes and the actin cytoskeleton in setting up oocyte cell polarity for ACD and potentially also for future embryonic development. In the proposed research, we plan to build on these exciting recent findings to answer three mechanistic questions: 1) how actin dynamics drive oocyte symmetry breaking (Aim1); 2) how the nuclear genome directly signals morphological reorganization on the cellular level (Aim2); and 3) how an unusual mechanism of dynamic force production patterns a large cell (the oocyte) and potentially impacts organelle segregation and early embryonic development (Aim3). To answer these questions, we will employ a highly innovative approach that entails a full integration of molecular genetic methods with cutting-edge imaging technologies, biophysical tools and mathematical analysis. Because clinical evidence suggests that defects in the polarized organization of mature oocytes are associated with aging-related infertility, our study not only has the potential for novel intellectual contribution to the understanding of self-organization in cellular systems but may also provide the basis for future development of new methods that help improve human fertility and prevent birth defects.