Ovarian Germline Stem Cells (OGSCs) and the Hippo Signaling Pathway Association with Physiological and Pathological Ovarian Aging in Mice
Ovarian Germline Stem Cells (OGSCs) and the Hippo Signaling Pathway Association with Physiological and Pathological Ovarian Aging in Mice
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卵巢生殖干细胞 (OGSC) 和 Hippo 信号通路与小鼠卵巢生理和病理衰老的关系
DOI：
10.1159/000430144
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发表时间：
2015-01-01
影响因子：
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通讯作者：
Zheng, Yuehui
中科院分区：
文献类型：
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作者：
Li, Jia;Zhou, Fangyue;Zheng, Yuehui
背景资料：Hippo信号通路在多种组织中的干细胞维持中起着重要作用，因此对干细胞生物学具有影响。这一最近发现的通路的关键成分已被证明与原始卵泡激活有关。然而，Hippo信号通路是否在小鼠生理和病理性卵巢衰老过程中卵巢生殖干细胞（OGSC）的发育中发挥作用尚不清楚。研究方法：分别选用7日龄（7 D）、2月龄、10月龄、20月龄（2 M、10 M、20 M）小鼠和2月龄TPT、CY/BUS药物处理小鼠作为生理性和病理性卵巢衰老模型。采用免疫组织化学方法检测卵泡发育情况，免疫荧光、Western印迹和实时荧光定量PCR方法检测OGSC与MST 1、LATS 2和YAP 1的共定位。结果：Hippo信号通路基因和MVH/OCT 4基因在小鼠卵巢皮质共表达。LATS 2、MST 1、MVH和OCT 4的水平和共定位随着年龄的增加而显著降低，但是YAP 1在2 M小鼠的小鼠卵巢皮质中比7 D小鼠更普遍，并且在20 M小鼠中未观察到。此外，YAP 1，MVH和OCT 4在TPT和CY/BUS处理后逐渐降低，LATS 2 mRNA和蛋白质的上调在TPT和CY/BUS处理的小鼠中持续存在。而TPT组和CY/BUS组MST 1的表达均低于对照组。此外，与20 M小鼠相比，pYAP 1蛋白在7 D小鼠卵巢皮质中的表达最高，且pYAP 1/YAP 1值从7 D到20 M逐渐降低。此外，在TPT和CY/BUS处理组中，pYAP 1降低，但pYAP 1/YAP 1值在这些组中升高。结论：总之，我们的研究结果表明，海马信号通路与小鼠生理和病理卵巢衰老过程中OGSC发生的变化有关。因此，Hippo信号通路可能参与OGSC的发育时间表。
Background: The Hippo signaling pathway plays fundamental roles in stem cell maintenance in a variety of tissues and has thus implications for stem cell biology. Key components of this recently discovered pathway have been shown to be associated with primordial follicle activation. However, whether the Hippo signaling pathway plays a role in the development of Ovarian Germline Stem Cells (OGSCs) during physiological and pathological ovarian aging in mice is unknown. Methods: Mice at the age of 7 days (7D), or of 2, 10, or 20 months (2M, 10M, 20M) and mice at 2M treated with TPT and CY/BUS drugs were selected as physiological and pathological ovarian aging models, respectively. Immunohistochemistry was used to assess the development of follicles, and the co-localization of genes characteristic of OGSCs with MST1, LATS2 and YAP1 was assessed by immunofluorescence, western blotting and real-time PCR methods. Results: The Hippo signal pathway and MVH/OCT4 genes were co-expressed in the mouse ovarian cortex. The level and co-localization of LATS2, MST1, MVH, and OCT4 were significantly decreased with increased age, but YAP1 was more prevalent in the mouse ovarian cortex of 2M mice than 7D mice and was not observed in 20M mice. Furthermore, YAP1, MVH, and OCT4 were gradually decreased after TPT and CY/BUS treatment, and LATS2 mRNA and protein up-regulation persisted in TPT- and CY/BUS-treated mice. However, the expression of MST1 was lower in the TPT and CY/BUS groups compared with the control group. In addition, pYAP1 protein showed the highest expression in the ovarian cortexes of 7D mice compared with 20M mice, and the value of pYAP1/YAP1 decreased from 7D to 20M. Moreover, pYAP1 decreased in the TPT- and CY/BUS-treated groups, but the value of pYAP1/YAP1 increased in these groups. Conclusion: Taken together, our results show that the Hippo signaling pathway is associated with the changes that take place in OGSCs during physiological and pathological ovarian aging in mice. Thus, the Hippo signaling pathway may be involved in the development schedule of OGSCs.