Control of Oocyte Maturation in C. elegans

卵母细胞减数分裂成熟是有性繁殖所必需的。卵母细胞减数分裂成熟的定义是 终变期(减数分裂前期的最后阶段)与减数分裂I和IS中期之间的过渡 伴随着核膜破裂、皮质细胞骨架重排和减数分裂纺锤体 集合。在许多物种中，激素通过调节CDK/Cyclin、MAPK和 GAS调节的蛋白激酶A通路。性腺的体细胞也在调节 减数分裂成熟。尽管如此，我们对细胞间信号如何控制减数分裂的了解仍有许多空白。 并为受精的卵母细胞做好准备。最近的减数分裂信号的鉴定已经证明 在哺乳动物系统中具有挑战性，这些未表征的信号如何 已收到并已处理。雌性减数分裂I的染色体错误分离是导致 流产和唐氏综合症和最近的研究指出，卵子发生过程中的激素信号缺陷 这是人类非整倍体的重要原因。 我们实验室的工作已经确立了线虫秀丽线虫作为一种重要的 研究卵母细胞减数分裂成熟信号。我们的研究表明，线虫的精子输出 主要精子蛋白(MSP)通过囊泡萌发机制触发卵母细胞MAPK激活和 减数分裂成熟。MSP还促进围绕卵母细胞的滤泡状鞘细胞的收缩。 在之前的资助阶段，我们发现卵母细胞中的Eph/MSP受体通路具有拮抗作用 鞘细胞中的Gao/I和Gas蛋白信号通路调节减数分裂成熟 MSP。下一个资助期的主要目标将是阐明MSP的生物化学和细胞生物学 说明卵母细胞和鞘细胞如何协调整合MSP减数分裂成熟信号。 为了实现这些目标，我们将：1)阐明MSP/VAB-1 Eph受体的分子决定因素 2)确定内吞作用在MSP/Eph受体信号转导卵母细胞减数分裂成熟中的作用； 确定性腺鞘细胞如何与VAB-1平行地调节减数分裂成熟。自.以来 发育信号机制和细胞周期机制是进化保守的，研究 线虫模型系统将增强我们对人类生殖的理解。

Oocyte meiotic maturation is required for sexual reproduction. Oocyte meiotic maturation is defined by the transition between diakinesis (final stage of meiotic prophase) and metaphase of meiosis I and is accompanied by nuclear envelope breakdown, cortical cytoskeletal rearrangement, and meiotic spindle assembly. In many species, hormones trigger meiotic maturation by regulating CDK/cyclin, MAP kinase, and Gas-regulated protein kinase A pathways. Somatic cells of the gonad also play critical roles in regulating meiotic maturation. Still, there are many gaps in our knowledge of how intercellular signals control meiotic progression and prepare the oocyte for fertilization. Identification of the proximate meiotic signals has proved challenging in mammalian systems and it remains to be determined how these uncharacterized signals are received and processed. Chromosome missegregation in female meiosis I represents the leading cause of miscarriage and Down syndrome and recent work points to hormonal signaling deficits during oogenesis as a significant cause of aneuploidy in humans. Work in our laboratory has established the nematode Caenorhaditis elegans as an important system for studying oocyte meiotic maturation signaling. Our studies demonstrate that C. elegans sperm export the major sperm protein (MSP) by a vesicle budding mechanism to trigger oocyte MAP kinase activation and meiotic maturation. MSP also promotes the contraction of the follicle-like sheath cells that surround oocytes. In the prior funding period, we discovered that an Eph/MSP receptor pathway in the oocyte andantagonistic Gao/i and Gas protein signaling pathways in the sheath cells regulate meiotic maturation in response to MSP. Major goals for the next funding period will be elucidating the biochemistry and cell biology of MSP signaling to address how oocyte and sheath cells coordinately integrate the MSP meiotic maturation signal. To achieve these goals, we will: 1) Elucidate the molecular determinants of the MSP/VAB-1 Eph receptor interaction; 2) Define the role of endocytosis in MSP/Eph receptor signaling for oocyte meiotic maturation;3) Determine how the gonadal sheath cells regulate meiotic maturation in parallel to VAB-1. Since developmental signaling mechanisms and the cell cycle machinery are evolutionary conserved, studies in the C. elegans model system will enhance our understanding of human reproduction.