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Retinoblastoma protein promotes uterine epithelial cell cycle arrest and necroptosis for embryo invasion
Author(s) -
Akaeda Shun,
Hirota Yasushi,
Fukui Yamato,
Aikawa Shizu,
ShimizuHirota Ryoko,
Kaku Tetsuaki,
Gebril Mona,
Hirata Tomoyuki,
Hiraoka Takehiro,
Matsuo Mitsunori,
Haraguchi Hirofumi,
SaitoKanatani Mayuko,
Takeda Norihiko,
Fujii Tomoyuki,
Osuga Yutaka
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202050927
Subject(s) - necroptosis , embryo , biology , microbiology and biotechnology , retinoblastoma protein , epithelium , programmed cell death , downregulation and upregulation , cancer research , cell cycle , apoptosis , genetics , gene
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, TNFα‐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. 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.