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Aberrant activation of KRAS in mouse theca-interstitial cells results in female infertility
KRAS plays critical roles in regulating a range of normal cellular events as well as pathological processes in many tissues mediated through a variety of signaling pathways, including ERK1/2 and AKT signaling, in a cell-, context- and development-dependent manner. The in vivo function of KRAS and it...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9437434/ https://www.ncbi.nlm.nih.gov/pubmed/36060690 http://dx.doi.org/10.3389/fphys.2022.991719 |
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author | Sun, Penghao Wang, Hongliang Liu, Lingyun Guo, Kaimin Li, Xian Cao, Yin Ko, Chemyong Lan, Zi-Jian Lei, Zhenmin |
author_facet | Sun, Penghao Wang, Hongliang Liu, Lingyun Guo, Kaimin Li, Xian Cao, Yin Ko, Chemyong Lan, Zi-Jian Lei, Zhenmin |
author_sort | Sun, Penghao |
collection | PubMed |
description | KRAS plays critical roles in regulating a range of normal cellular events as well as pathological processes in many tissues mediated through a variety of signaling pathways, including ERK1/2 and AKT signaling, in a cell-, context- and development-dependent manner. The in vivo function of KRAS and its downstream targets in gonadal steroidogenic cells for the development and homeostasis of reproductive functions remain to be determined. To understand the functions of KRAS signaling in gonadal theca and interstitial cells, we generated a Kras mutant (tKrasMT) mouse line that selectively expressed a constitutively active Kras ( G12D ) in these cells. Kras ( G12D ) expression in ovarian theca cells did not block follicle development to the preovulatory stage. However, tKrasMT females failed to ovulate and thus were infertile. The phosphorylated ERK1/2 and forkhead box O1 (FOXO1) and total FOXO1 protein levels were markedly reduced in tKrasMT theca cells. Kras ( G12D ) expression in theca cells also curtailed the phosphorylation of ERK1/2 and altered the expression of several ovulation-related genes in gonadotropin-primed granulosa cells. To uncover downstream targets of KRAS/FOXO1 signaling in theca cells, we found that the expression of bone morphogenic protein 7 (Bmp7), a theca-specific factor involved in ovulation, was significantly elevated in tKrasMT theca cells. Chromosome immunoprecipitation assays demonstrated that FOXO1 interacted with the Bmp7 promoter containing forkhead response elements and that the binding activity was attenuated in tKrasMT theca cells. Moreover, Foxo1 knockdown caused an elevation, whereas Foxo1 overexpression resulted in an inhibition of Bmp7 expression, suggesting that KRAS signaling regulates FOXO1 protein levels to control Bmp7 expression in theca cells. Thus, the anovulation phenotype observed in tKrasMT mice may be attributed to aberrant KRAS/FOXO1/BMP7 signaling in theca cells. Our work provides the first in vivo evidence that maintaining normal KRAS activity in ovarian theca cells is crucial for ovulation and female fertility. |
format | Online Article Text |
id | pubmed-9437434 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94374342022-09-03 Aberrant activation of KRAS in mouse theca-interstitial cells results in female infertility Sun, Penghao Wang, Hongliang Liu, Lingyun Guo, Kaimin Li, Xian Cao, Yin Ko, Chemyong Lan, Zi-Jian Lei, Zhenmin Front Physiol Physiology KRAS plays critical roles in regulating a range of normal cellular events as well as pathological processes in many tissues mediated through a variety of signaling pathways, including ERK1/2 and AKT signaling, in a cell-, context- and development-dependent manner. The in vivo function of KRAS and its downstream targets in gonadal steroidogenic cells for the development and homeostasis of reproductive functions remain to be determined. To understand the functions of KRAS signaling in gonadal theca and interstitial cells, we generated a Kras mutant (tKrasMT) mouse line that selectively expressed a constitutively active Kras ( G12D ) in these cells. Kras ( G12D ) expression in ovarian theca cells did not block follicle development to the preovulatory stage. However, tKrasMT females failed to ovulate and thus were infertile. The phosphorylated ERK1/2 and forkhead box O1 (FOXO1) and total FOXO1 protein levels were markedly reduced in tKrasMT theca cells. Kras ( G12D ) expression in theca cells also curtailed the phosphorylation of ERK1/2 and altered the expression of several ovulation-related genes in gonadotropin-primed granulosa cells. To uncover downstream targets of KRAS/FOXO1 signaling in theca cells, we found that the expression of bone morphogenic protein 7 (Bmp7), a theca-specific factor involved in ovulation, was significantly elevated in tKrasMT theca cells. Chromosome immunoprecipitation assays demonstrated that FOXO1 interacted with the Bmp7 promoter containing forkhead response elements and that the binding activity was attenuated in tKrasMT theca cells. Moreover, Foxo1 knockdown caused an elevation, whereas Foxo1 overexpression resulted in an inhibition of Bmp7 expression, suggesting that KRAS signaling regulates FOXO1 protein levels to control Bmp7 expression in theca cells. Thus, the anovulation phenotype observed in tKrasMT mice may be attributed to aberrant KRAS/FOXO1/BMP7 signaling in theca cells. Our work provides the first in vivo evidence that maintaining normal KRAS activity in ovarian theca cells is crucial for ovulation and female fertility. Frontiers Media S.A. 2022-08-19 /pmc/articles/PMC9437434/ /pubmed/36060690 http://dx.doi.org/10.3389/fphys.2022.991719 Text en Copyright © 2022 Sun, Wang, Liu, Guo, Li, Cao, Ko, Lan and Lei. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Sun, Penghao Wang, Hongliang Liu, Lingyun Guo, Kaimin Li, Xian Cao, Yin Ko, Chemyong Lan, Zi-Jian Lei, Zhenmin Aberrant activation of KRAS in mouse theca-interstitial cells results in female infertility |
title | Aberrant activation of KRAS in mouse theca-interstitial cells results in female infertility |
title_full | Aberrant activation of KRAS in mouse theca-interstitial cells results in female infertility |
title_fullStr | Aberrant activation of KRAS in mouse theca-interstitial cells results in female infertility |
title_full_unstemmed | Aberrant activation of KRAS in mouse theca-interstitial cells results in female infertility |
title_short | Aberrant activation of KRAS in mouse theca-interstitial cells results in female infertility |
title_sort | aberrant activation of kras in mouse theca-interstitial cells results in female infertility |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9437434/ https://www.ncbi.nlm.nih.gov/pubmed/36060690 http://dx.doi.org/10.3389/fphys.2022.991719 |
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