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:	Mu-Hang Li, Leilani M. Marty-Santos, Paul R. van Ginkel, Aubrey E. McDermott, Andrew J. Rasky, Nicholas W. Lukacs, Deneen M. Wellik
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Hox genes lung homeostasis extracellular matrix distal lung fibroblasts lung macrophages brochopulmonary dysplasia Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/4881e5a53fd44504b5e9e770a665a0b8
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spelling	oai:doaj.org-article:4881e5a53fd44504b5e9e770a665a0b82021-12-01T07:33:31ZThe Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function2296-634X10.3389/fcell.2021.767454https://doaj.org/article/4881e5a53fd44504b5e9e770a665a0b82021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.767454/fullhttps://doaj.org/toc/2296-634XHox 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; Hox5afafbbcc 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.Mu-Hang LiLeilani M. Marty-SantosPaul R. van GinkelAubrey E. McDermottAndrew J. RaskyNicholas W. LukacsDeneen M. WellikFrontiers Media S.A.articleHox geneslung homeostasisextracellular matrixdistal lung fibroblastslung macrophagesbrochopulmonary dysplasiaBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Hox genes lung homeostasis extracellular matrix distal lung fibroblasts lung macrophages brochopulmonary dysplasia Biology (General) QH301-705.5
spellingShingle	Hox genes lung homeostasis extracellular matrix distal lung fibroblasts lung macrophages brochopulmonary dysplasia Biology (General) QH301-705.5 Mu-Hang Li Leilani M. Marty-Santos Paul R. van Ginkel Aubrey E. McDermott Andrew J. Rasky Nicholas W. Lukacs Deneen M. Wellik The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function
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; Hox5afafbbcc 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.
format	article
author	Mu-Hang Li Leilani M. Marty-Santos Paul R. van Ginkel Aubrey E. McDermott Andrew J. Rasky Nicholas W. Lukacs Deneen M. Wellik
author_facet	Mu-Hang Li Leilani M. Marty-Santos Paul R. van Ginkel Aubrey E. McDermott Andrew J. Rasky Nicholas W. Lukacs Deneen M. Wellik
author_sort	Mu-Hang Li
title	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_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_sort	lung elastin matrix undergoes rapid degradation upon adult loss of hox5 function
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/4881e5a53fd44504b5e9e770a665a0b8
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The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function

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