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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...

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Autores principales: Ni, Nan, Gao, Yang, Fang, Xin, Melgar, Maria, Vincent, David F., Lydon, John P., Bartholin, Laurent, Li, Qinglei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
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.
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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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