SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production.
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.
Chen
Gang
G
The Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati School of Medicine, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
Korfhagen
Thomas R
TR
Xu
Yan
Y
Kitzmiller
Joseph
J
Wert
Susan E
SE
Maeda
Yutaka
Y
Gregorieff
Alexander
A
Clevers
Hans
H
Whitsett
Jeffrey A
JA
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D020397:Goblet Cells / Q000166:cytology / Q000502:physiology*; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology / Q000502:physiology; D008171:Lung Diseases / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009077:Mucins / Q000096:biosynthesis / Q000235:genetics; D009088:Mucoproteins / Q000235:genetics / Q000378:metabolism; D009093:Mucus / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology* / Q000502:physiology
C526445:Agr2 protein, mouse; C496506:Foxa3 protein, mouse; D009077:Mucins; D009088:Mucoproteins; D015513:Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; C519908:Spdef protein, mouse; D051543:Hepatocyte Nuclear Factor 3-gamma