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The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function

Hox genes encode transcription factors that are critical for embryonic skeletal patterning and organogenesis. The Hoxa5, Hoxb5, and Hoxc5 paralogs are expressed in the lung mesenchyme and function redundantly during embryonic lung development. Conditional loss-of-function of these genes during postn...

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Autores principales: Li, Mu-Hang, Marty-Santos, Leilani M., van Ginkel, Paul R., McDermott, Aubrey E., Rasky, Andrew J., Lukacs, Nicholas W., Wellik, Deneen M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8662386/
https://www.ncbi.nlm.nih.gov/pubmed/34901011
http://dx.doi.org/10.3389/fcell.2021.767454
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author Li, Mu-Hang
Marty-Santos, Leilani M.
van Ginkel, Paul R.
McDermott, Aubrey E.
Rasky, Andrew J.
Lukacs, Nicholas W.
Wellik, Deneen M.
author_facet Li, Mu-Hang
Marty-Santos, Leilani M.
van Ginkel, Paul R.
McDermott, Aubrey E.
Rasky, Andrew J.
Lukacs, Nicholas W.
Wellik, Deneen M.
author_sort Li, Mu-Hang
collection PubMed
description Hox genes encode transcription factors that are critical for embryonic skeletal patterning and organogenesis. The Hoxa5, Hoxb5, and Hoxc5 paralogs are expressed in the lung mesenchyme and function redundantly during embryonic lung development. Conditional loss-of-function of these genes during postnatal stages leads to severe defects in alveologenesis, specifically in the generation of the elastin network, and animals display bronchopulmonary dysplasia (BPD) or BPD-like phenotype. Here we show the surprising results that mesenchyme-specific loss of Hox5 function at adult stages leads to rapid disruption of the mature elastin matrix, alveolar enlargement, and an emphysema-like phenotype. As the elastin matrix of the lung is considered highly stable, adult disruption of the matrix was not predicted. Just 2 weeks after deletion, adult Hox5 mutant animals show significant increases in alveolar space and changes in pulmonary function, including reduced elastance and increased compliance. Examination of the extracellular matrix (ECM) of adult Tbx4rtTA; TetOCre; Hox5a(f)a(f)bbcc lungs demonstrates a disruption of the elastin network although the underlying fibronectin, interstitial collagen and basement membrane appear unaffected. An influx of macrophages and increased matrix metalloproteinase 12 (MMP12) are observed in the distal lung 3 days after Hox5 deletion. In culture, fibroblasts from Hox5 mutant lungs exhibit reduced adhesion. These findings establish a novel role for Hox5 transcription factors as critical regulators of lung fibroblasts at adult homeostasis.
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spelling pubmed-86623862021-12-11 The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function Li, Mu-Hang Marty-Santos, Leilani M. van Ginkel, Paul R. McDermott, Aubrey E. Rasky, Andrew J. Lukacs, Nicholas W. Wellik, Deneen M. Front Cell Dev Biol Cell and Developmental Biology Hox genes encode transcription factors that are critical for embryonic skeletal patterning and organogenesis. The Hoxa5, Hoxb5, and Hoxc5 paralogs are expressed in the lung mesenchyme and function redundantly during embryonic lung development. Conditional loss-of-function of these genes during postnatal stages leads to severe defects in alveologenesis, specifically in the generation of the elastin network, and animals display bronchopulmonary dysplasia (BPD) or BPD-like phenotype. Here we show the surprising results that mesenchyme-specific loss of Hox5 function at adult stages leads to rapid disruption of the mature elastin matrix, alveolar enlargement, and an emphysema-like phenotype. As the elastin matrix of the lung is considered highly stable, adult disruption of the matrix was not predicted. Just 2 weeks after deletion, adult Hox5 mutant animals show significant increases in alveolar space and changes in pulmonary function, including reduced elastance and increased compliance. Examination of the extracellular matrix (ECM) of adult Tbx4rtTA; TetOCre; Hox5a(f)a(f)bbcc lungs demonstrates a disruption of the elastin network although the underlying fibronectin, interstitial collagen and basement membrane appear unaffected. An influx of macrophages and increased matrix metalloproteinase 12 (MMP12) are observed in the distal lung 3 days after Hox5 deletion. In culture, fibroblasts from Hox5 mutant lungs exhibit reduced adhesion. These findings establish a novel role for Hox5 transcription factors as critical regulators of lung fibroblasts at adult homeostasis. Frontiers Media S.A. 2021-11-26 /pmc/articles/PMC8662386/ /pubmed/34901011 http://dx.doi.org/10.3389/fcell.2021.767454 Text en Copyright © 2021 Li, Marty-Santos, van Ginkel, McDermott, Rasky, Lukacs and Wellik. 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 Cell and Developmental Biology
Li, Mu-Hang
Marty-Santos, Leilani M.
van Ginkel, Paul R.
McDermott, Aubrey E.
Rasky, Andrew J.
Lukacs, Nicholas W.
Wellik, Deneen M.
The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function
title The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function
title_full The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function
title_fullStr The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function
title_full_unstemmed The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function
title_short The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function
title_sort lung elastin matrix undergoes rapid degradation upon adult loss of hox5 function
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8662386/
https://www.ncbi.nlm.nih.gov/pubmed/34901011
http://dx.doi.org/10.3389/fcell.2021.767454
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