Study on the change in FSH-induced signaling pathway involved in granulosa cell survival and death

虽然绝大多数卵泡都经历了一种称为闭锁的退化过程，但这种闭锁过程的基本机制仍不清楚。卵巢颗粒细胞(GC)的存活和凋亡对决定排卵卵泡的数量起着至关重要的作用。卵泡刺激素(FSH)被认为是GCs存活和卵泡生长的关键因素。我们的实验室最近发现，在卵泡发育过程中，FSH诱导的细胞外调节激酶(ERK)的激活以cAMP依赖的方式转变为cAMP非依赖的途径。ERK是第一个被发现的MAP激酶。本研究的目的是更详细地研究FSH诱导ERK激活的途径，包括改变对cAMP依赖的意义。溶血磷脂酸是血清的一种成分，可诱导对cAMP依赖性的改变。在成熟卵泡和未成熟卵泡中，磷脂酶C的激活分别是FSH诱导分化和未分化GCs ERK激活的关键，这与以往的报道不一致。CAMP不是分化的GCs生存所必需的，而是促进了细胞的凋亡。依赖FSH的GCs的生存需要ERK和p38的活性，ERK和p38是另一种类型的MAPK。有趣的是，p38的激活也与氧化应激诱导的GCs的凋亡有关。

Although the vast majority of ovarian follicles undergo a degenerative process termed atresia, the fundamental mechanism of this atretic process is largely unknown. Survival and apoptosis of ovarian granulosa cells (GCs) play a crucial role in determining the number of follicles destined to ovulate. Follicle-stimulating hormone (FSH) is thought to be a critical factor for the survival of GCs and follicular growth. Our laboratory recently found that FSH-induced activation of extracellular-regulated kinase (ERK), which is first identified MAP kinase, is changed in a cAMP-dependent to a cAMP-independent pathway during follicular development. The aim of this study is to examine the pathway of FSH-induced ERK activation in more detail, involving the meaning of the change in the dependency on cAMP.We have obtained the following results.1. Lysophosphatidic acid, a component of the serum, induced the change in the dependency on cAMP.2. Activation of phospholipase C was essential for FSH-elicited ERK activation in both differentiated and undifferentiated GCs prepared from mature and immature follicles, respectively, which is inconsistent with previous reports.3. cAMP was not necessary for the survival of differentiated GCs, rather promoted apoptosis.4. FSH-dependent survival of GCs requires the activities of ERK and p38, another type of MAP kinases. Interestingly, p38 activation is also implicated in apoptosis of GCs induced by oxidative stress.