Retinoblastoma protein promotes uterine epithelial cell cycle arrest and necroptosis for embryo invasion
Retinoblastoma protein promotes uterine epithelial cell cycle arrest and necroptosis for embryo invasion
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DOI：
10.15252/embr.202050927
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发表时间：
2021-01-05
期刊：
影响因子：
7.7
通讯作者：
Osuga, Yutaka
中科院分区：
文献类型：
--
作者：
Akaeda, Shun;Hirota, Yasushi;Osuga, Yutaka
Rb1编码的视网膜母细胞瘤蛋白(Rb)是细胞周期停滞(CCA)的重要诱导物。激素孕酮(P-4)促进子宫上皮中的CCA，先前的研究表明，P-4通过减少磷酸化的、非活性的Rb来激活Rb。在这里，我们展示了子宫特异性Rb1基因敲除小鼠的胚胎着床受到损害。我们观察到Rb1缺陷的子宫上皮细胞持续增殖直到胚胎附着，上皮细胞坏死下垂和滋养层细胞吞噬功能的丧失，这与随后的胚胎侵袭失败相关，表明Rb1诱导的CCA和子宫上皮的坏死下垂参与了胚胎侵袭。植入前补充P-4足以修复这些缺陷和胚胎侵袭。在Rb1缺乏的子宫上皮细胞中，肿瘤坏死因子α诱导的坏死性下垂受到损害，而CCA诱导剂胸腺嘧啶核苷或P-4通过上调肿瘤坏死因子受体2型的表达而被挽救。肿瘤坏死因子α在子宫腔上皮和胚胎附着部位表达。这些结果提供证据表明，子宫Rb1诱导的CCA参与了肿瘤坏死因子α诱导的着床部位上皮坏死下垂，从而成功地实现了胚胎的侵袭。
Retinoblastoma protein (RB) encoded by Rb1 is a prominent inducer of cell cycle arrest (CCA). The hormone progesterone (P-4) promotes CCA in the uterine epithelium and previous studies indicated that P-4 activates RB by reducing the phosphorylated, inactive form of RB. Here, we show that embryo implantation is impaired in uterine-specific Rb1 knockout mice. We observe persistent cell proliferation of the Rb1-deficient uterine epithelium until embryo attachment, loss of epithelial necroptosis, and trophoblast phagocytosis, which correlates with subsequent embryo invasion failure, indicating that Rb1-induced CCA and necroptosis of uterine epithelium are involved in embryo invasion. Pre-implantation P-4 supplementation is sufficient to restore these defects and embryo invasion. In Rb1-deficient uterine epithelial cells, TNF alpha-primed necroptosis is impaired, which is rescued by the treatment with a CCA inducer thymidine or P-4 through the upregulation of TNF receptor type 2. TNF alpha is expressed in the luminal epithelium and the embryo at the embryo attachment site. These results provide evidence that uterine Rb1-induced CCA is involved in TNF alpha-primed epithelial necroptosis at the implantation site for successful embryo invasion.