Loss of MIG-6 results in endometrial progesterone resistance via ERBB2

Jung-Yoon Yoo; Tae Hoon Kim; Jung-Ho Shin; Ryan M Marquardt; Ulrich Müller; Asgerally T Fazleabas; Steven L Young; Bruce A Lessey; Ho-Geun Yoon; Jae-Wook Jeong

doi:10.1038/s41467-022-28608-x

Loss of MIG-6 results in endometrial progesterone resistance via ERBB2

Nat Commun. 2022 Mar 1;13(1):1101. doi: 10.1038/s41467-022-28608-x.

Authors

Jung-Yoon Yoo^#^{1

2}, Tae Hoon Kim^#¹, Jung-Ho Shin³, Ryan M Marquardt^{1

4}, Ulrich Müller⁵, Asgerally T Fazleabas¹, Steven L Young⁶, Bruce A Lessey⁷, Ho-Geun Yoon⁸, Jae-Wook Jeong⁹

Affiliations

¹ Department of Obstetrics,Gynecology & Reproductive Biology, Michigan State University, College of Human Medicine, Grand Rapids, MI, USA.
² Department of Biomedical Laboratory Science, Yonsei University Mirae Campus, Wonju, South Korea.
³ Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, Guro Hospital, Korea University Medical Center, Seoul, South Korea.
⁴ Cell and Molecular Biology Program, Michigan State University, East Lansing, MI, USA.
⁵ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC, USA.
⁷ Department of Obstetrics and Gynecology, Wake Forest Baptist Health, Winston-Salem, NC, USA.
⁸ Department 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. yhgeun@yuhs.ac.
⁹ Department of Obstetrics,Gynecology & Reproductive Biology, Michigan State University, College of Human Medicine, Grand Rapids, MI, USA. jeongj@msu.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Endometriosis* / genetics
Endometriosis* / metabolism
Endometrium / abnormalities
Endometrium / metabolism
Female
Infertility, Female* / genetics
Infertility, Female* / metabolism
Intracellular Signaling Peptides and Proteins* / deficiency
Intracellular Signaling Peptides and Proteins* / metabolism
Mice
Progesterone / metabolism
Receptor, ErbB-2* / genetics
Receptor, ErbB-2* / metabolism
Receptors, Progesterone / genetics
Receptors, Progesterone / metabolism
Uterine Diseases* / genetics
Uterine Diseases* / metabolism

Substances

Errfi1 protein, mouse
Intracellular Signaling Peptides and Proteins
Receptors, Progesterone
Progesterone
Erbb2 protein, mouse
Receptor, ErbB-2

Supplementary concepts

Progesterone Resistance

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding