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Mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development

BACKGROUND: Adenomatous polyposis coli (Apc) is a tumor suppressor that inhibits Wnt/Ctnnb1. Mutations of Apc will not only lead to familial adenomatous polyposis with associated epithelial lesions, but will also cause aggressive fibromatosis in mesenchymal cells. However, the roles of Apc in regula...

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Autores principales: Luo, Yongfeng, El Agha, Elie, Turcatel, Gianluca, Chen, Hui, Chiu, Joanne, Warburton, David, Bellusci, Saverio, Qian, Bang-Ping, Menke, Douglas B., Shi, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702410/
https://www.ncbi.nlm.nih.gov/pubmed/26092405
http://dx.doi.org/10.1186/s12915-015-0153-1
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author Luo, Yongfeng
El Agha, Elie
Turcatel, Gianluca
Chen, Hui
Chiu, Joanne
Warburton, David
Bellusci, Saverio
Qian, Bang-Ping
Menke, Douglas B.
Shi, Wei
author_facet Luo, Yongfeng
El Agha, Elie
Turcatel, Gianluca
Chen, Hui
Chiu, Joanne
Warburton, David
Bellusci, Saverio
Qian, Bang-Ping
Menke, Douglas B.
Shi, Wei
author_sort Luo, Yongfeng
collection PubMed
description BACKGROUND: Adenomatous polyposis coli (Apc) is a tumor suppressor that inhibits Wnt/Ctnnb1. Mutations of Apc will not only lead to familial adenomatous polyposis with associated epithelial lesions, but will also cause aggressive fibromatosis in mesenchymal cells. However, the roles of Apc in regulating mesenchymal cell biology and organogenesis during development are unknown. RESULTS: We have specifically deleted the Apc gene in lung mesenchymal cells during early lung development in mice. Loss of Apc function resulted in immediate mesenchymal cell hyperproliferation through abnormal activation of Wnt/Ctnnb1, followed by a subsequent inhibition of cell proliferation due to cell cycle arrest at G0/G1, which was caused by a mechanism independent of Wnt/Ctnnb1. Meanwhile, abrogation of Apc also disrupted lung mesenchymal cell differentiation, including decreased airway and vascular smooth muscle cells, the presence of Sox9-positive mesenchymal cells in the peripheral lung, and excessive versican production. Moreover, lung epithelial branching morphogenesis was drastically inhibited due to disrupted Bmp4-Fgf10 morphogen production and regulation in surrounding lung mesenchyme. Lastly, lung mesenchyme-specific Apc conditional knockout also resulted in altered lung vasculogenesis and disrupted pulmonary vascular continuity through a paracrine mechanism, leading to massive pulmonary hemorrhage and lethality at mid-gestation when the pulmonary circulation should have started. CONCLUSIONS: Our study suggests that Apc in lung mesenchyme plays central roles in coordinating the proper development of several quite different cellular compartments including lung epithelial branching and pulmonary vascular circulation during lung organogenesis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12915-015-0153-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-47024102016-01-07 Mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development Luo, Yongfeng El Agha, Elie Turcatel, Gianluca Chen, Hui Chiu, Joanne Warburton, David Bellusci, Saverio Qian, Bang-Ping Menke, Douglas B. Shi, Wei BMC Biol Research Article BACKGROUND: Adenomatous polyposis coli (Apc) is a tumor suppressor that inhibits Wnt/Ctnnb1. Mutations of Apc will not only lead to familial adenomatous polyposis with associated epithelial lesions, but will also cause aggressive fibromatosis in mesenchymal cells. However, the roles of Apc in regulating mesenchymal cell biology and organogenesis during development are unknown. RESULTS: We have specifically deleted the Apc gene in lung mesenchymal cells during early lung development in mice. Loss of Apc function resulted in immediate mesenchymal cell hyperproliferation through abnormal activation of Wnt/Ctnnb1, followed by a subsequent inhibition of cell proliferation due to cell cycle arrest at G0/G1, which was caused by a mechanism independent of Wnt/Ctnnb1. Meanwhile, abrogation of Apc also disrupted lung mesenchymal cell differentiation, including decreased airway and vascular smooth muscle cells, the presence of Sox9-positive mesenchymal cells in the peripheral lung, and excessive versican production. Moreover, lung epithelial branching morphogenesis was drastically inhibited due to disrupted Bmp4-Fgf10 morphogen production and regulation in surrounding lung mesenchyme. Lastly, lung mesenchyme-specific Apc conditional knockout also resulted in altered lung vasculogenesis and disrupted pulmonary vascular continuity through a paracrine mechanism, leading to massive pulmonary hemorrhage and lethality at mid-gestation when the pulmonary circulation should have started. CONCLUSIONS: Our study suggests that Apc in lung mesenchyme plays central roles in coordinating the proper development of several quite different cellular compartments including lung epithelial branching and pulmonary vascular circulation during lung organogenesis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12915-015-0153-1) contains supplementary material, which is available to authorized users. BioMed Central 2015-06-20 /pmc/articles/PMC4702410/ /pubmed/26092405 http://dx.doi.org/10.1186/s12915-015-0153-1 Text en © Luo et al. 2015 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 work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Luo, Yongfeng
El Agha, Elie
Turcatel, Gianluca
Chen, Hui
Chiu, Joanne
Warburton, David
Bellusci, Saverio
Qian, Bang-Ping
Menke, Douglas B.
Shi, Wei
Mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development
title Mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development
title_full Mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development
title_fullStr Mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development
title_full_unstemmed Mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development
title_short Mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development
title_sort mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702410/
https://www.ncbi.nlm.nih.gov/pubmed/26092405
http://dx.doi.org/10.1186/s12915-015-0153-1
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