TY - JOUR
T1 - Retinoblastoma protein promotes uterine epithelial cell cycle arrest and necroptosis for embryo invasion
AU - Akaeda, Shun
AU - Hirota, Yasushi
AU - Fukui, Yamato
AU - Aikawa, Shizu
AU - Shimizu-Hirota, Ryoko
AU - Kaku, Tetsuaki
AU - Gebril, Mona
AU - Hirata, Tomoyuki
AU - Hiraoka, Takehiro
AU - Matsuo, Mitsunori
AU - Haraguchi, Hirofumi
AU - Saito-Kanatani, Mayuko
AU - Takeda, Norihiko
AU - Fujii, Tomoyuki
AU - Osuga, Yutaka
N1 - Funding Information:
We thank NCI mouse repository for providing ‐floxed mice, Dr. Francesco J. DeMayo (National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA) and Dr. John P. Lydon (Baylor College of Medicine, Houston, TX, USA) for providing ‐Cre mice, Dr. Sudhansu K. Dey (Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA) for providing ‐Cre mice, Dr. Satoru Fukuda (The University of Tokyo, Japan) for technical assistance of TEM, Ms. Katie A. Gerhardt for efficient editing of the manuscript, and Ms. Atsumi Miura for technical assistance. This work was supported by JSPS KAKENHI (grant numbers 19H03144, 18K19601, 19H03796, 18K19600, 18H02943, 19K16022, 19K18631, 19K18630, 20K08894) and AMED‐Force (20gm4010010h0001), AMED‐Wise (20gk0210021h0002), Takeda Science Foundation, and the fund of joint research with NIPRO corporation. Rb1 Pgr Ltf
Funding Information:
We thank NCI mouse repository for providing Rb1-floxed mice, Dr. Francesco J. DeMayo (National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA) and Dr. John P. Lydon (Baylor College of Medicine, Houston, TX, USA) for providing Pgr-Cre mice, Dr. Sudhansu K. Dey (Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA) for providing Ltf-Cre mice, Dr. Satoru Fukuda (The University of Tokyo, Japan) for technical assistance of TEM, Ms. Katie A. Gerhardt for efficient editing of the manuscript, and Ms. Atsumi Miura for technical assistance. This work was supported by JSPS KAKENHI (grant numbers 19H03144, 18K19601, 19H03796, 18K19600, 18H02943, 19K16022, 19K18631, 19K18630, 20K08894) and AMED-Force (20gm4010010h0001), AMED-Wise (20gk0210021h0002), Takeda Science Foundation, and the fund of joint research with NIPRO corporation.
Publisher Copyright:
© 2021 The Authors
PY - 2021/2/3
Y1 - 2021/2/3
N2 - 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.
AB - 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.
KW - TNFα signaling
KW - embryo implantation
KW - progesterone
KW - trophoblast phagocytosis
KW - uterine luminal epithelium
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U2 - 10.15252/embr.202050927
DO - 10.15252/embr.202050927
M3 - Article
C2 - 33399260
AN - SCOPUS:85099101032
SN - 1469-221X
VL - 22
JO - EMBO Reports
JF - EMBO Reports
IS - 2
M1 - e50927
ER -