Semaphorin6c 通过细胞连接调节次级卵泡发育成熟和闭锁机制的研究

The increasing of the secondary follicles atresia and decreasing of the oocytes quality during the perimenopausal period of female, which induced by the asynchronous maturation of the granulosa cells (GCs) and oocyte, were considered to be the major reason of the ovarian function deficient and accelerating of the ovarian aging process. And the low expression of Semaphorin (Sema6c) expression in the elder mouse ovaries was profiled to induce the asynchronous maturation of the GCs and oocyte of the secondary follicles, yet the mechanisms and targets were still unknown. The Semas family was verified to regulate the cell junction through Rho-GTPases and PI3K/Akt pathway in the nervous system and cardiovascular system, yet their functions and mechanisms were rarely mentioned in the ovary. Meanwhile, the cell junction would be important target of hormone and cytokines inside and outside of the ovaries to regulate development and atresia of ovarian follicles. So we down- and up- regulated the Sema6c expression in the follicle in vivo and in vitro, then detected and regulated the activity of RhoGTPase and PI3K/AKT pathway, and changes of the cell junction to exploring the function and mechanism that Sema6c regulated synchronous maturation of the secondary follicles, and providing evidence for new target of the ovarian aging process.

围绝经期卵巢中次级卵泡颗粒细胞与卵母细胞非同步发育成熟所导致卵母细胞质量下降和次级卵泡闭锁增加是卵巢加速衰老的主要原因。我们早期研究发现小鼠卵巢衰老过程中低表达的Semaphorin6c（Sema6c）与次级卵泡中颗粒细胞和卵母细胞非同步发育成熟密切相关，然而具体作用机制及靶点仍不明确。在神经系统和心血管系统，Semas家族可通过Rho-GTP酶和PI3K/Akt等信号通路对细胞连接发挥广泛的调节作用，在卵巢中却鲜有提及。而细胞连接正是卵巢内外细胞因子和激素调节卵泡发育成熟和闭锁的重要靶点。因此本研究拟通过体内外实验上调/下调小鼠卵泡中Sema6c的表达以及细胞内通路的检测和干预，探讨Sema6c对卵泡中细胞连接的调节作用及分子机制，进一步阐释Sema6c调节次级卵泡细胞同步发育成熟的分子机制，为寻找衰老导致卵巢功能不良的作用新靶点提供理论依据。

围绝经期卵巢中次级卵泡颗粒细胞与卵母细胞非同步发育成熟所导致卵母细胞质量下降和次级卵泡闭锁增加是卵巢加速衰老的主要原因。我们早期研究发现小鼠卵巢衰老过程中低表达的Semaphorin6c（Sema6c）与次级卵泡中颗粒细胞和卵母细胞非同步发育成熟密切相关，然而具体作用机制及靶点仍不明确。在神经系统和心血管系统，Semas家族可通过Rho-GTP酶和PI3K/Akt等信号通路对细胞连接发挥广泛的调节作用，在卵巢中却鲜有提及。而细胞连接正是卵巢内外细胞因子和激素调节卵泡发育成熟和闭锁的重要靶点。因此本研究通过体内外实验证实Sema6c通过PI3K/Akt信号通路调节卵泡细胞中细胞连接的形成，从而调节卵泡细胞的闭锁和发育成熟,进而参与小鼠卵巢功能和卵巢衰老进程的调节过程，可能作为调节衰老导致卵巢功能不良的新靶点。