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SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production
Gang Chen, … , Hans Clevers, Jeffrey A. Whitsett
Gang Chen, … , Hans Clevers, Jeffrey A. Whitsett
Published September 14, 2009
Citation Information: J Clin Invest. 2009;119(10):2914-2924. https://doi.org/10.1172/JCI39731.
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Research Article Development Article has an altmetric score of 4

SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production

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Abstract

Various acute and chronic inflammatory stimuli increase the number and activity of pulmonary mucus-producing goblet cells, and goblet cell hyperplasia and excess mucus production are central to the pathogenesis of chronic pulmonary diseases. However, little is known about the transcriptional programs that regulate goblet cell differentiation. Here, we show that SAM-pointed domain–containing Ets-like factor (SPDEF) controls a transcriptional program critical for pulmonary goblet cell differentiation in mice. Initial cell-lineage–tracing analysis identified nonciliated secretory epithelial cells, known as Clara cells, as the progenitors of goblet cells induced by pulmonary allergen exposure in vivo. Furthermore, in vivo expression of SPDEF in Clara cells caused rapid and reversible goblet cell differentiation in the absence of cell proliferation. This was associated with enhanced expression of genes regulating goblet cell differentiation and protein glycosylation, including forkhead box A3 (Foxa3), anterior gradient 2 (Agr2), and glucosaminyl (N-acetyl) transferase 3, mucin type (Gcnt3). Consistent with these findings, levels of SPDEF and FOXA3 were increased in mouse goblet cells after sensitization with pulmonary allergen, and the proteins were colocalized in goblet cells lining the airways of patients with chronic lung diseases. Deletion of the mouse Spdef gene resulted in the absence of goblet cells in tracheal/laryngeal submucosal glands and in the conducting airway epithelium after pulmonary allergen exposure in vivo. These data show that SPDEF plays a critical role in regulating a transcriptional network mediating the goblet cell differentiation and mucus hyperproduction associated with chronic pulmonary disorders.

Authors

Gang Chen, Thomas R. Korfhagen, Yan Xu, Joseph Kitzmiller, Susan E. Wert, Yutaka Maeda, Alexander Gregorieff, Hans Clevers, Jeffrey A. Whitsett

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Figure 2

mRNA microarray analysis of bronchiolar epithelial cells: heat map and partial list of SPDEF-regulated genes.

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mRNA microarray analysis of bronchiolar epithelial cells: heat map and p...
Bronchiolar cells were isolated by LCM and mRNAs isolated and subjected to mRNA microarray analysis after treating Scgb1a1-rtTA/TRE2-Spdef mice for 3 days with or without doxycycline. (A) Heat map of the mRNAs. Red indicates mRNAs increased by SPDEF; green indicates those decreased. A number of mRNAs that were previously associated with pulmonary allergen exposure, including Foxa3, Gcnt3, Clca1, Agr2, Ptger3, and Muc16 were induced by SPDEF. SPDEF inhibited genes selectively expressed in normal airway epithelial cells, including Abca3, Sftpa1, Sftpb, Sftpd, and Foxa2 (A). Quantitative RT-PCR was performed in triplicate using cDNAs obtained from bronchiolar cells by LCM. Spdef mRNA was induced by doxycycline treatment (B). SPDEF induced Muc16 (C), Gcnt3 (D), Clca1 (E), and Ptger3 (F) mRNAs. Results were expressed as mean ± SD of 3 independent mice for each treatment. *P < 0.05 versus off-doxycycline control littermates (Hsu’s MCB test).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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