Control of Oocyte Maturation in C. elegans

描述（由申请人提供）：有性生殖需要卵母细胞减数分裂成熟。卵母细胞减数分裂成熟是由减数分裂末期（减数分裂前期的最后阶段）和减数分裂中期之间的过渡所定义的，并伴随着核膜的破裂、皮质细胞骨架的重排和减数分裂纺锤体的组装。在许多物种中，激素通过调节CDK/细胞周期蛋白、MAP激酶和气体调节的蛋白激酶A途径触发减数分裂成熟。性腺的体细胞在调节减数分裂成熟中也起着关键作用。尽管如此，我们对细胞间信号如何控制减数分裂进程并为卵母细胞受精做准备的知识仍有许多空白。在哺乳动物系统中，鉴定近似减数分裂信号已被证明是具有挑战性的，如何接收和处理这些未表征的信号仍有待确定。女性减数分裂I中的染色体错误分离是流产和唐氏综合征的主要原因，最近的研究表明，卵子发生过程中的激素信号缺陷是人类非整倍体的重要原因。本实验室的工作已经建立了秀丽隐杆线虫作为研究卵母细胞减数分裂成熟信号的重要系统。我们的研究表明，秀丽隐杆线虫精子通过囊泡出芽机制输出主要精子蛋白（MSP），从而触发卵母细胞MAP激酶激活和减数分裂成熟。MSP还能促进卵母细胞周围的卵泡样鞘细胞的收缩。在之前的资助期内，我们发现卵母细胞中的Eph/MSP受体通路和鞘细胞中的拮抗Gao/i和Gas蛋白信号通路在MSP的作用下调节减数分裂成熟。下一个资助期的主要目标将是阐明MSP信号的生物化学和细胞生物学，以解决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受体相互作用的分子决定因素；2)明确内吞作用在卵母细胞减数分裂成熟过程中MSP/Eph受体信号传导中的作用；3)确定性腺鞘细胞如何与VAB-1平行调节减数分裂成熟。由于发育信号机制和细胞周期机制是进化保守的，对秀丽隐杆线虫模型系统的研究将增强我们对人类生殖的理解。

DESCRIPTION (provided by applicant): 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 and antagonistic 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.