151. WNT/RYK signaling restricts goblet cell differentiation during lung development and repair.
- Author
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Kim HT, Yin W, Nakamichi Y, Panza P, Grohmann B, Buettner C, Guenther S, Ruppert C, Kobayashi Y, Guenther A, and Stainier DYR
- Subjects
- A549 Cells, Animals, Humans, Hyperplasia metabolism, Hyperplasia pathology, Mice, Mucus metabolism, Pneumonia metabolism, Pneumonia pathology, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Disease, Chronic Obstructive pathology, beta Catenin metabolism, Cell Differentiation physiology, Goblet Cells cytology, Goblet Cells metabolism, Goblet Cells physiology, Lung cytology, Lung growth & development, Lung metabolism, Receptor Protein-Tyrosine Kinases metabolism, Wnt Signaling Pathway physiology
- Abstract
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 N -ethyl- N -nitrosourea (ENU) screen for modulators of postnatal lung development; Ryk 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 Ryk deletion causes goblet cell hyperplasia and mucus hypersecretion but not inflammation, while club cell-specific Ryk 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., Competing Interests: The authors declare no competing interest.
- Published
- 2019
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