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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	1101
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-28608-x
State	Published - Dec 2022

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/s41467-022-28608-x

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@article{6209ef188c114a688f6faa1b9ea7a795,

title = "Loss of MIG-6 results in endometrial progesterone resistance via ERBB2",

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 (Pgrcre/+Mig-6f/f; Mig-6d/d). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb2 ablation in Mig-6d/d mice (Mig-6d/dErbb2d/d mice). The additional knockout of Erbb2 rescues all phenotypes seen in Mig-6d/d mice. Transcriptomic analysis shows that genes differentially expressed in Mig-6d/d mice revert to their normal expression in Mig-6d/dErbb2d/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.",

author = "Yoo, {Jung Yoon} and Kim, {Tae Hoon} and Shin, {Jung Ho} and Marquardt, {Ryan M.} and Ulrich M{\"u}ller and Fazleabas, {Asgerally T.} and Young, {Steven L.} and Lessey, {Bruce A.} and Yoon, {Ho Geun} and Jeong, {Jae Wook}",

note = "Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MIST) (No. 2018R1A5A2025079 and 2020R1A2C3003303 to H.-G.Y.), and SRI and Bayer Discovery/Innovation Grant (to T.H.K.), as well as by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Numbers R01HD084478, R01HD101243, and R01HD102170 (to J.W.J) and F31HD101207 and T32HD087166 (to R.M.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-28608-x",

language = "English (US)",

volume = "13",

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AU - Yoo, Jung Yoon

AU - Kim, Tae Hoon

AU - Shin, Jung Ho

AU - Marquardt, Ryan M.

AU - Müller, Ulrich

AU - Fazleabas, Asgerally T.

AU - Young, Steven L.

AU - Lessey, Bruce A.

AU - Yoon, Ho Geun

AU - Jeong, Jae Wook

N1 - Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MIST) (No. 2018R1A5A2025079 and 2020R1A2C3003303 to H.-G.Y.), and SRI and Bayer Discovery/Innovation Grant (to T.H.K.), as well as by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Numbers R01HD084478, R01HD101243, and R01HD102170 (to J.W.J) and F31HD101207 and T32HD087166 (to R.M.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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 (Pgrcre/+Mig-6f/f; Mig-6d/d). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb2 ablation in Mig-6d/d mice (Mig-6d/dErbb2d/d mice). The additional knockout of Erbb2 rescues all phenotypes seen in Mig-6d/d mice. Transcriptomic analysis shows that genes differentially expressed in Mig-6d/d mice revert to their normal expression in Mig-6d/dErbb2d/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.

AB - 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 (Pgrcre/+Mig-6f/f; Mig-6d/d). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb2 ablation in Mig-6d/d mice (Mig-6d/dErbb2d/d mice). The additional knockout of Erbb2 rescues all phenotypes seen in Mig-6d/d mice. Transcriptomic analysis shows that genes differentially expressed in Mig-6d/d mice revert to their normal expression in Mig-6d/dErbb2d/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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JO - Nature Communications

JF - Nature Communications

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ER -

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

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