Journal article

Publication year: 2019

Pages: 25697-25706

Journal: Proceedings of the National Academy of Sciences

Volume number: 116

Issue number: 51

ISSN: 0027-8424

Open access status: Green

DOI Link: https://doi.org/10.1073/pnas.1911071116

Publisher: National Academy of Sciences

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/beta-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.

Harvard Citation style: Kim, H., Yin, W., Nakamichi, Y., Panza, P., Grohmann, B., Buettner, C., et al. (2019) WNT/RYK signaling restricts goblet cell differentiation during lung development and repair, Proceedings of the National Academy of Sciences, 116(51), pp. 25697-25706. https://doi.org/10.1073/pnas.1911071116

APA Citation style: Kim, H., Yin, W., Nakamichi, Y., Panza, P., Grohmann, B., Buettner, C., Guenther, S., Ruppert, C., Kobayashi, Y., Guenther, A., & Stainier, D. (2019). WNT/RYK signaling restricts goblet cell differentiation during lung development and repair. Proceedings of the National Academy of Sciences. 116(51), 25697-25706. https://doi.org/10.1073/pnas.1911071116