WNT/RYK signaling restricts goblet cell differentiation during lung development and repair
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- Hyun-Taek Kim
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany;
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- Wenguang Yin
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany;
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- Yuko Nakamichi
- Institute for Oral Science, Matsumoto Dental University, 399-0781 Shiojiri, Japan;
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- Paolo Panza
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany;
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- Beate Grohmann
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany;
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- Carmen Buettner
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany;
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- Stefan Guenther
- Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany;
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- Clemens Ruppert
- Biobank, University of Giessen & Marburg Lung Center, 35392 Giessen, Germany
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- Yasuhiro Kobayashi
- Institute for Oral Science, Matsumoto Dental University, 399-0781 Shiojiri, Japan;
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- Andreas Guenther
- Biobank, University of Giessen & Marburg Lung Center, 35392 Giessen, Germany
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- Didier Y. R. Stainier
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany;
説明
<jats:p> Goblet cell metaplasia and mucus hypersecretion are observed in many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the regulation of goblet cell differentiation remains unclear. Here, we identify a regulator of this process in an <jats:italic>N</jats:italic> -ethyl- <jats:italic>N</jats:italic> -nitrosourea (ENU) screen for modulators of postnatal lung development; <jats:italic>Ryk</jats:italic> mutant mice exhibit lung inflammation, goblet cell hyperplasia, and mucus hypersecretion. RYK functions as a WNT coreceptor, and, in the developing lung, we observed high RYK expression in airway epithelial cells and moderate expression in mesenchymal cells as well as in alveolar epithelial cells. From transcriptomic analyses and follow-up studies, we found decreased WNT/β-catenin signaling activity in the mutant lung epithelium. Epithelial-specific <jats:italic>Ryk</jats:italic> deletion causes goblet cell hyperplasia and mucus hypersecretion but not inflammation, while club cell-specific <jats:italic>Ryk</jats:italic> deletion in adult stages leads to goblet cell hyperplasia and mucus hypersecretion during regeneration. We also found that the airway epithelium of COPD patients often displays goblet cell metaplastic foci, as well as reduced RYK expression. Altogether, our findings reveal that RYK plays important roles in maintaining the balance between airway epithelial cell populations during development and repair, and that defects in RYK expression or function may contribute to the pathogenesis of human lung diseases. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 116 (51), 25697-25706, 2019-11-27
Proceedings of the National Academy of Sciences
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詳細情報 詳細情報について
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- CRID
- 1360849943791865984
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- ISSN
- 10916490
- 00278424
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- データソース種別
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- Crossref
- KAKEN