期刊
JOURNAL OF MOLECULAR CELL BIOLOGY
卷 13, 期 9, 页码 646-661出版社
OXFORD UNIV PRESS
DOI: 10.1093/jmcb/mjab034
关键词
IGF1R; IGF1; IGF2; uterine epithelium; implantation; blastocyst
类别
资金
- National Key R&D Program of China [2017YFC1001402, 2018YFC1004401]
- National Natural Science Foundation of China [81830045, 82030040, 81971388]
- Institution of Higher Education Projects of Building First-class Discipline Construction in Ningxia Region [NXYLXK2017B05]
This study revealed the crucial role of IGF1R in the uterus during pregnancy, which is essential for normal epithelial differentiation and embryo implantation.
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 stromat 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.
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