Crucial role of high-mobility group box 2 in mouse ovarian follicular development through estrogen receptor beta
Crucial role of high-mobility group box 2 in mouse ovarian follicular development through estrogen receptor beta
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DOI：
10.1007/s00418-022-02074-4
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发表时间：
2022-01-13
影响因子：
2.3
通讯作者：
Hishikawa, Yoshitaka
中科院分区：
文献类型：
--
作者：
Yamaguma, Yu;Sugita, Naohiro;Hishikawa, Yoshitaka
高迁移率族蛋白2（HMGB 2）是一种染色质相关蛋白，是基因转录、重组和修复过程的重要调节因子。HMGB 2的功能重要性已被报道在各种器官，包括睾丸，心脏和软骨。然而，它在卵巢中的作用在很大程度上是未知的。在这项研究中，卵巢组织从野生型（WT）和HMGB 2基因敲除（KO）小鼠进行了检查组织病理学染色和免疫组化。HMGB 2-KO小鼠的卵巢大小和重量显著低于年龄匹配的WT同窝小鼠。组织学分析显示，10月龄HMGB 2-KO小鼠卵巢出现卵巢萎缩和进行性纤维化。与年龄匹配的WT小鼠相比，HMGB 2-KO小鼠的卵母细胞和发育卵泡数量在2月龄时显著减少，并在10月龄时完全耗尽。免疫组化结果显示HMGB 2在卵泡颗粒细胞、卵母细胞、黄体和间质细胞中均有表达。重要的是，HMGB 2阳性细胞与雌激素受体β（ER β）共定位，而不是ER α。雌激素反应元件结合活性通过西南组织化学证实，并且在HMGB 2-KO小鼠卵巢中降低。HMGB 2-KO小鼠卵巢中的细胞增殖活性也降低，与卵泡生成减少平行。这些结果表明，HMGB 2的耗竭诱导卵巢萎缩，其特征在于卵巢大小和重量减少、进行性纤维化以及卵母细胞和卵泡发生减少。总之，我们证明了HMGB 2通过ER β表达在小鼠卵泡发生中的关键作用。
High-mobility group box 2 (HMGB2) is a chromatin-associated protein that is an important regulator of gene transcription, recombination, and repair processes. The functional importance of HMGB2 has been reported in various organs, including the testis, heart, and cartilage. However, its role in the ovary is largely unknown. In this study, ovary tissues from wild-type (WT) and HMGB2-knock-out (KO) mice were examined by histopathological staining and immunohistochemistry. The ovary size and weight were significantly lower in HMGB2-KO mice than in age-matched WT littermates. Histopathological analysis revealed ovarian atrophy and progressive fibrosis in 10-month-old HMGB2-KO mouse ovaries. Compared to age-matched WT mice, the numbers of oocytes and developing follicles were significantly decreased at 2 months of age and were completely depleted at 10 months of age in HMGB2-KO mice. Immunohistochemistry revealed the expression of HMGB2 in the granulosa cells of developing follicles, oocytes, some corpora lutea, and stromal cells. Importantly, HMGB2-positive cells were co-localized with estrogen receptor beta (ER beta), but not ER alpha. Estrogen response element-binding activity was demonstrated by southwestern histochemistry, and it was decreased in HMGB2-KO mouse ovaries. Cell proliferation activity was also decreased in HMGB2-KO mouse ovaries in parallel with the decreased folliculogenesis. These results indicated that the depletion of HMGB2 induced ovarian atrophy that was characterized by a decreased ovarian size and weight, progressive fibrosis, as well as decreased oocytes and folliculogenesis. In conclusion, we demonstrated the crucial role of HMGB2 in mouse ovarian folliculogenesis through ER beta expression.