Retinoblastoma protein promotes uterine epithelial cell cycle arrest and necroptosis for embryo invasion

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.

Automated summary

Progesterone promotes cell cycle arrest, with RB protein playing a crucial role in embryo implantation. Uterine-specific Rb1 knockout mice show persistent cell proliferation and reduced necroptosis, leading to impaired embryo invasion. Pre-implantation P-4 supplementation can restore these defects and promote successful embryo invasion by enhancing TNF alpha-primed epithelial necroptosis.