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Nat. Commun., 2022 Mar 1;13(1):1101 | https://doi.org/10.1038/s41467-022-28608-x Loss of MIG-6 results in endometrial progesterone resistance via ERBB2

Jung-Yoon Yoo^1,2,9, Tae Hoon Kim^1,9, Jung-Ho Shin³, Ryan M. Marquardt^1,4, Ulrich Müller⁵, Asgerally T. Fazleabas¹, Steven L. Young⁶, Bruce A. Lessey⁷, Ho-Geun Yoon^8,* & Jae-Wook Jeong^1,*

¹Department of Obstetrics,Gynecology & Reproductive Biology, Michigan State University, College of Human Medicine, Grand Rapids, MI, USA. ²Department of Biomedical Laboratory Science, Yonsei University Mirae Campus, Wonju, South Korea. ³Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, Guro Hospital, Korea University Medical Center, Seoul, South Korea. ⁴Cell and Molecular Biology Program, Michigan State University, East Lansing, MI, USA. ⁵The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ⁶Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC, USA. ⁷Department of Obstetrics and Gynecology, Wake Forest Baptist Health, Winston-Salem, NC, USA. ⁸Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea. ⁹These authors contributed equally: Jung-Yoon Yoo, Tae Hoon Kim.

^*Corresponding author.

Abstract

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/dErbb2^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/dErbb2^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.

논문정보

형식Research article
게재일2022년 03월 (BRIC 등록일 2022-03-11)
연구진국내(교신)+국외 연구진
분야 의약학 > 분자세포의학

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