A negative feedback system between oocyte bone morphogenetic protein 15 and granulosa cell kit ligand: Its role in regulating granulosa cell mitosis
A negative feedback system between oocyte bone morphogenetic protein 15 and granulosa cell kit ligand: Its role in regulating granulosa cell mitosis
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DOI：
10.1073/pnas.122066899
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发表时间：
2002-06-11
影响因子：
11.1
通讯作者：
Shimasaki, S
中科院分区：
文献类型：
--
作者：
Otsuka, F;Shimasaki, S
虽然在卵母细胞和卵泡体细胞之间存在调节性旁分泌反馈系统已经被假定了一段时间，但还没有任何明确的证据表明存在这样的通信系统。在此，我们提出了一个以前未描述的卵母细胞-颗粒细胞（GC）反馈通信系统，涉及卵母细胞衍生的因子，骨形态发生蛋白-15（BMP-15）和GC衍生的因子，试剂盒配体（KL），这两个已被证明是女性生殖的重要调节因子。我们使用了大鼠卵母细胞和GCs的共培养系统，发现BMP-15刺激GCs中KL的表达，而KL抑制卵母细胞中BMP-15的表达，从而形成负反馈回路。此外，KL，像BMP-15，表现出有丝分裂活动的GC在卵母细胞的存在下。由于c-kit（KL受体）在卵母细胞中表达而在GC中不表达，因此卵母细胞必须参与介导KL诱导的GC有丝分裂。此外，通过使用c-kit中和抗体阻断卵母细胞中的c-kit信号传导显著抑制BMP-15诱导的GC有丝分裂，表明卵母细胞必须在GC对BMP-15的反应中发挥作用。相反，c-kit抗体对另外两种已知的GC有丝分裂原激活素A和BMP-7的有丝分裂活性没有影响。总之，本研究提供了由卵母细胞衍生的BMP-15和GC衍生的KL控制的负反馈系统的直接证据，并表明BMP-15和KL对GC的有丝分裂活性依赖于该卵母细胞-GC通信系统。我们推测负反馈系统很可能在早期卵泡发生中起关键作用。
Although the existence of a regulatory paracrine feedback system between oocytes and follicular somatic cells has been postulated for some time, there has not yet been any definitive evidence that such a communication system exists. Herein we present a previously undescribed oocyte-granulosa cell (GC) feedback communication system involving an oocyte-derived factor, bone morphogenetic protein-15 (BMP-15) and a GC-derived factor, kit ligand (KL), both of which have been shown to be crucial regulators of female reproduction. We used a coculture system of rat oocytes and GCs and found that BMP-15 stimulates KL expression in GCs, whereas KL inhibits BMP-15 expression in oocytes, thus forming a negative feedback loop. Moreover, KL, like BMP-15, exhibited mitotic activity on GCs in the presence of oocytes. Because c-kit (KL receptor) is expressed in oocytes but not GCs, the oocytes must be involved in mediating the KL-induced GC mitosis. Furthermore, the blockage of c-kit signaling in oocytes by using a c-kit neutralizing antibody markedly suppressed BMP-15-induced GC mitosis, suggesting that the oocyte must play a role in the GC responses to BMP-15. In contrast, the c-kit antibody had no effect on the mitotic activities of two other known GC mitogens, activin-A and BMP-7. Altogether, this study presents direct evidence of a negative feedback system governed by oocyte-derived BMP-15 and GC-derived KL, and demonstrates that the mitotic activities of BMP-15 and KL for GCs depend on this oocyte-GC communication system. We hypothesize that the negative feedback system most likely plays a pivotal role in early folliculogenesis.