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Glandular defects in the mouse uterus with sustained activation of TGF-beta signaling is associated with altered differentiation of endometrial stromal cells and formation of stromal compartment
Uterine gland development, also known as adenogenesis, is a key uterine morphogenic process indispensable for normal uterine function and fertility. Our earlier studies have reported that overactivation of TGFB receptor 1 (TGFBR1) in the mouse uterus using progesterone receptor (Pgr)-Cre recombinase...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294433/ https://www.ncbi.nlm.nih.gov/pubmed/30550590 http://dx.doi.org/10.1371/journal.pone.0209417 |
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author | Ni, Nan Gao, Yang Fang, Xin Melgar, Maria Vincent, David F. Lydon, John P. Bartholin, Laurent Li, Qinglei |
author_facet | Ni, Nan Gao, Yang Fang, Xin Melgar, Maria Vincent, David F. Lydon, John P. Bartholin, Laurent Li, Qinglei |
author_sort | Ni, Nan |
collection | PubMed |
description | Uterine gland development, also known as adenogenesis, is a key uterine morphogenic process indispensable for normal uterine function and fertility. Our earlier studies have reported that overactivation of TGFB receptor 1 (TGFBR1) in the mouse uterus using progesterone receptor (Pgr)-Cre recombinase causes female infertility, defective decidualization, and reduced uterine gland formation, a developmental milestone of postnatal uterus. To understand mechanisms that underpin the disrupted uterine gland formation in mice with sustained activation of TGFBR1, we raised the question of whether early postnatal adenogenesis was compromised in these mice. Experiments were designed using mice with constitutive activation of TGFBR1 driven by Pgr-Cre to determine the timing of adenogenic defects and potential mechanisms associated with dysregulation of adenogenic genes, luminal epithelial cell proliferation and endometrial fibrotic changes. Uterine tissues from mice with constitutive activation of TGFBR1 were collected during the critical time window of adenogenesis and analyzed together with age-matched controls. Multiple approaches including immunohistochemistry, immunofluorescence, Trichrome staining, quantitative real-time PCR, western blot, conditional knockout and human endometrial cell culture were utilized. TGFBR1 activation in the mouse uterus suppressed adenogenesis during postnatal uterine development, concomitant with the aberrant differentiation of uterine stromal cells. Analysis of transcript expression of WNT pathway components revealed dysregulation of adenogenesis-associated genes. Notably, the adenogenic defects occurred in spite of the increased proliferation of uterine luminal epithelial cells, accompanied by increased expression of genes associated with fibrotic changes. Moreover, the adenogenic defects were alleviated in mice where TGFBR1 was activated in presumably half of the complement of uterine cells. Our results suggest that altered differentiation of endometrial stromal cells and formation of stromal compartment promote adenogenic defects. |
format | Online Article Text |
id | pubmed-6294433 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-62944332018-12-28 Glandular defects in the mouse uterus with sustained activation of TGF-beta signaling is associated with altered differentiation of endometrial stromal cells and formation of stromal compartment Ni, Nan Gao, Yang Fang, Xin Melgar, Maria Vincent, David F. Lydon, John P. Bartholin, Laurent Li, Qinglei PLoS One Research Article Uterine gland development, also known as adenogenesis, is a key uterine morphogenic process indispensable for normal uterine function and fertility. Our earlier studies have reported that overactivation of TGFB receptor 1 (TGFBR1) in the mouse uterus using progesterone receptor (Pgr)-Cre recombinase causes female infertility, defective decidualization, and reduced uterine gland formation, a developmental milestone of postnatal uterus. To understand mechanisms that underpin the disrupted uterine gland formation in mice with sustained activation of TGFBR1, we raised the question of whether early postnatal adenogenesis was compromised in these mice. Experiments were designed using mice with constitutive activation of TGFBR1 driven by Pgr-Cre to determine the timing of adenogenic defects and potential mechanisms associated with dysregulation of adenogenic genes, luminal epithelial cell proliferation and endometrial fibrotic changes. Uterine tissues from mice with constitutive activation of TGFBR1 were collected during the critical time window of adenogenesis and analyzed together with age-matched controls. Multiple approaches including immunohistochemistry, immunofluorescence, Trichrome staining, quantitative real-time PCR, western blot, conditional knockout and human endometrial cell culture were utilized. TGFBR1 activation in the mouse uterus suppressed adenogenesis during postnatal uterine development, concomitant with the aberrant differentiation of uterine stromal cells. Analysis of transcript expression of WNT pathway components revealed dysregulation of adenogenesis-associated genes. Notably, the adenogenic defects occurred in spite of the increased proliferation of uterine luminal epithelial cells, accompanied by increased expression of genes associated with fibrotic changes. Moreover, the adenogenic defects were alleviated in mice where TGFBR1 was activated in presumably half of the complement of uterine cells. Our results suggest that altered differentiation of endometrial stromal cells and formation of stromal compartment promote adenogenic defects. Public Library of Science 2018-12-14 /pmc/articles/PMC6294433/ /pubmed/30550590 http://dx.doi.org/10.1371/journal.pone.0209417 Text en © 2018 Ni et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Ni, Nan Gao, Yang Fang, Xin Melgar, Maria Vincent, David F. Lydon, John P. Bartholin, Laurent Li, Qinglei Glandular defects in the mouse uterus with sustained activation of TGF-beta signaling is associated with altered differentiation of endometrial stromal cells and formation of stromal compartment |
title | Glandular defects in the mouse uterus with sustained activation of TGF-beta signaling is associated with altered differentiation of endometrial stromal cells and formation of stromal compartment |
title_full | Glandular defects in the mouse uterus with sustained activation of TGF-beta signaling is associated with altered differentiation of endometrial stromal cells and formation of stromal compartment |
title_fullStr | Glandular defects in the mouse uterus with sustained activation of TGF-beta signaling is associated with altered differentiation of endometrial stromal cells and formation of stromal compartment |
title_full_unstemmed | Glandular defects in the mouse uterus with sustained activation of TGF-beta signaling is associated with altered differentiation of endometrial stromal cells and formation of stromal compartment |
title_short | Glandular defects in the mouse uterus with sustained activation of TGF-beta signaling is associated with altered differentiation of endometrial stromal cells and formation of stromal compartment |
title_sort | glandular defects in the mouse uterus with sustained activation of tgf-beta signaling is associated with altered differentiation of endometrial stromal cells and formation of stromal compartment |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294433/ https://www.ncbi.nlm.nih.gov/pubmed/30550590 http://dx.doi.org/10.1371/journal.pone.0209417 |
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