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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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.767454/full |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-17T20:50:00Z |
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| id | doaj.art-4881e5a53fd44504b5e9e770a665a0b8 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-17T20:50:00Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-4881e5a53fd44504b5e9e770a665a0b82022-12-21T21:33:03ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-11-01910.3389/fcell.2021.767454767454The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 FunctionMu-Hang Li0Leilani M. Marty-Santos1Paul R. van Ginkel2Aubrey E. McDermott3Andrew J. Rasky4Nicholas W. Lukacs5Deneen M. Wellik6Genetics Training Program, University of Wisconsin-Madison, Madison, WI, United StatesDepartment of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United StatesDepartment of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United StatesDepartment of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United StatesDepartment of Pathology, University of Michigan, Ann Arbor, MI, United StatesDepartment of Pathology, University of Michigan, Ann Arbor, MI, United StatesDepartment of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United StatesHox 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.https://www.frontiersin.org/articles/10.3389/fcell.2021.767454/fullHox geneslung homeostasisextracellular matrixdistal lung fibroblastslung macrophagesbrochopulmonary dysplasia |
| spellingShingle | 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 Frontiers in Cell and Developmental Biology Hox genes lung homeostasis extracellular matrix distal lung fibroblasts lung macrophages brochopulmonary dysplasia |
| 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 | Hox genes lung homeostasis extracellular matrix distal lung fibroblasts lung macrophages brochopulmonary dysplasia |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.767454/full |
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