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Sequential activation of uterine epithelial IGF1R by stromal IGF1 and embryonic IGF2 directs normal uterine preparation for embryo implantation

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Journal of Molecular Cell Biology 2021年第9期13卷 646-661页

作者： Chan Zhou Meiying Lv Peike Wang Chuanhui Guo Zhangli Ni Haili Bao Yedong Tang Han Cai Jinhua Lu Wenbo Deng Xiaoyu Yang Guoliang Xia Haibin Wang Chao Wang Shuangbo Kong State Key Laboratory of Agrobiotechnology College of Biological SciencesChina Agricultural UniversityBeijingChina'2 Fujian Provincial Key Laboratory of Reproductive Health ResearchSchool of MedicineXiamen UniversityXiamenChina'3 Fuzhou Hospital of Traditional Chinese Medicine Affiliated to Fujian University of Traditional Chinese MedicineFuzhouChina'4 Department of Obstetrics and GynecologyThe First Affiliated Hospital of Xiamen UniversityXiamenChina'5 Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western ChinaCollege of Life ScienceNingXia UniversityYinchuanChina

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 Igflr 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.

关键词： IGF1R IGF1 IGF2 uterine epithelium implantation blastocyst

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