Retinoblastoma protein (RB) encoded by Rb1 is a prominent inducer of cell cycle arrest (CCA). The hormone progesterone (P₄) promotes CCA in the uterine epithelium and previous studies indicated that P₄ 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 P₄ supplementation is sufficient to restore these defects and embryo invasion. In Rb1‐deficient uterine epithelial cells, TNFα‐primed necroptosis is impaired, which is rescued by the treatment with a CCA inducer thymidine or P₄ through the upregulation of TNF receptor type 2. TNFα 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 TNFα‐primed epithelial necroptosis at the implantation site for successful embryo invasion.

中文翻译：

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视网膜母细胞瘤蛋白促进子宫上皮细胞周期停滞和胚胎侵袭的坏死性凋亡

由Rb1编码的视网膜母细胞瘤蛋白 (RB)是细胞周期停滞 (CCA) 的重要诱导剂。激素黄体酮 (P ₄ ) 促进子宫上皮细胞中的 CCA，以前的研究表明 P ₄通过减少磷酸化、无活性形式的 RB 来激活 RB。在这里，我们发现子宫特异性Rb1敲除小鼠的胚胎植入受损。我们观察到Rb1缺陷的子宫上皮细胞持续增殖直至胚胎附着、上皮坏死性凋亡和滋养层吞噬作用的丧失，这与随后的胚胎侵袭失败相关，表明Rb1诱导的CCA和子宫上皮坏死性凋亡与胚胎侵袭有关。植入前补充 P ₄足以恢复这些缺陷和胚胎侵袭。在Rb1缺陷的子宫上皮细胞中，TNFα 引发的坏死性凋亡受到损害，通过 2 型 TNF 受体的上调用 CCA 诱导剂胸苷或 P ₄治疗来挽救。TNFα 在腔上皮和胚胎中表达胚胎附着部位。这些结果提供了证据，表明子宫Rb1诱导的 CCA 参与了植入部位的 TNFα 引发的上皮坏死性凋亡，从而成功地侵入胚胎。