Loss of MIG-6 results in endometrial progesterone resistance via ERBB2open access
- Authors
- Yoo, Jung-Yoon; Kim, Tae Hoon; Shin, Jung-Ho; Marquardt, Ryan M.; Muller, Ulrich; Fazleabas, Asgerally T.; Young, Steven L.; Lessey, Bruce A.; Yoon, Ho-Geun; Jeong, Jae-Wook
- Issue Date
- 1-3월-2022
- Publisher
- NATURE PORTFOLIO
- Citation
- NATURE COMMUNICATIONS, v.13, no.1
- Indexed
- SCIE
SCOPUS
- Journal Title
- NATURE COMMUNICATIONS
- Volume
- 13
- Number
- 1
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/143903
- DOI
- 10.1038/s41467-022-28608-x
- ISSN
- 2041-1723
- Abstract
- Female subfertility is highly associated with endometriosis. Here the authors show that progesterone-induced MIG-6 is reduced in endometrium of infertile women and non-human primates with endometriosis, and in a mouse model find that Erbb2 is the key mediator of Mig-6 loss induced endometriosis-related infertility. Female subfertility is highly associated with endometriosis. Endometrial progesterone resistance is suggested as a crucial element in the development of endometrial diseases. We report that MIG-6 is downregulated in the endometrium of infertile women with endometriosis and in a non-human primate model of endometriosis. We find ERBB2 overexpression in the endometrium of uterine-specific Mig-6 knockout mice (Pgr(cre/+)Mig-6(f/f); Mig-6(d/d)). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb2 ablation in Mig-6(d/d) mice (Mig-6(d/d)Erbb2(d/d) mice). The additional knockout of Erbb2 rescues all phenotypes seen in Mig-6(d/d) mice. Transcriptomic analysis shows that genes differentially expressed in Mig-6(d/d) mice revert to their normal expression in Mig-6(d/d)Erbb2(d/d) mice. Together, our results demonstrate that ERBB2 overexpression in endometrium with MIG-6 deficiency causes endometrial progesterone resistance and a nonreceptive endometrium in endometriosis-related infertility, and ERBB2 targeting reverses these effects.
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