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Sequential activation of uterine epithelial IGF1R by stromal IGF1 and embryonic IGF2 directs normal uterine preparation for embryo implantation
Chan Zhou1,2 , Meiying Lv2,3 , Peike Wang1,2 , Chuanhui Guo1,2 , Zhangli Ni1,2 , Haili Bao2 , Yedong Tang2 , Han Cai2 , Jinhua Lu2,4 , Wenbo Deng2,4 , Xiaoyu Yang3 , Guoliang Xia1,5 , Haibin Wang2,4,* , Chao Wang1,* , Shuangbo Kong2,4,*
1State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
2Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen, China
3Fuzhou Hospital of Traditional Chinese Medicine Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, China
4Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, Xiamen, China
5Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, College of Life Science, NingXia University, Yinchuan, China
*Correspondence to:Haibin Wang , Chao Wang , Shuangbo Kong ,
J Mol Cell Biol, Volume 13, Issue 9, September 2021, 646-661,
Keyword: IGF1R, IGF1, IGF2, uterine epithelium, implantation, blastocyst
Embryo implantation in both humans and rodents is initiated by the attachment of a blastocyst to the uterine epithelium. For blastocyst attachment, the uterine epithelium needs to transform at both the structural and molecular levels first, and then initiate the interaction with trophectoderm. Any perturbation during this process will result in implantation failure or long-term adverse pregnancy outcomes. Endocrine steroid hormones, which function through nuclear receptors, combine with the local molecules produced by the uteri or embryo to facilitate implantation. The insulin-like growth factor (IGF) signaling has been reported to play a vital role during pregnancy. However, its physiological function during implantation remains elusive. This study revealed that mice with conditional deletion of Igf1r gene in uteri suffered from subfertility, mainly due to the disturbed uterine receptivity and abnormal embryo implantation. Mechanistically, we uncovered that in response to the nidatory estrogen on D4 of pregnancy, the epithelial IGF1R, stimulated by the stromal cell-produced IGF1, facilitated epithelial STAT3 activation to modulate the epithelial depolarity. Furthermore, embryonic derived IGF2 could activate both the epithelial ERK1/2 and STAT3 signaling through IGF1R, which was critical for the transcription of Cox2 and normal attachment reaction. In brief, our data revealed that epithelial IGF1R was sequentially activated by the uterine stromal IGF1 and embryonic IGF2 to guarantee normal epithelium differentiation during the implantation process.