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

被引:332
作者
Chen, Gang [1 ,2 ]
Korfhagen, Thomas R. [1 ,2 ]
Xu, Yan [1 ,2 ]
Kitzmiller, Joseph [1 ,2 ]
Wert, Susan E. [1 ,2 ]
Maeda, Yutaka [1 ,2 ]
Gregorieff, Alexander [3 ]
Clevers, Hans [3 ]
Whitsett, Jeffrey A. [1 ,2 ]
机构
[1] Cincinnati Childrens Hosp, Med Ctr, Div Pulm Biol, Perinatal Inst, Cincinnati, OH 45229 USA
[2] Univ Cincinnati, Sch Med, Cincinnati, OH USA
[3] Netherlands Inst Dev Biol, Utrecht, Netherlands
关键词
BRONCHIAL EPITHELIAL-CELLS; TRANSCRIPTION FACTOR; HUMAN AIRWAY; LUNG MORPHOGENESIS; MUCIN BIOSYNTHESIS; EXPRESSION; RECEPTOR; ASTHMA; GROWTH; IL-13;
D O I
10.1172/JCI39731
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:2914 / 2924
页数:11
相关论文
共 60 条
[1]   Laser capture microdissection and mRNA characterization of mouse airway epithelium: methodological considerations [J].
Betsuyaku, T ;
Senior, RM .
MICRON, 2004, 35 (04) :229-234
[2]   Mucin biosynthesis:: upregulation of core 2 β1,6 N-acetylglucosaminyltransferase by retinoic acid and Th2 cytokines in a human airway epithelial cell line [J].
Beum, PV ;
Basma, H ;
Bastola, DR ;
Cheng, PW .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2005, 288 (01) :L116-L124
[3]  
Beum PV, 2001, ADV EXP MED BIOL, V491, P279
[4]   Structural and functional analysis of domains mediating interaction between NKX-3.1 and PDEF [J].
Chen, H ;
Bieberich, CJ .
JOURNAL OF CELLULAR BIOCHEMISTRY, 2005, 94 (01) :168-177
[5]   MUC16 is produced in tracheal surface epithelium and submucosal glands and is present in secretions from normal human airway and cultured bronchial epithelial cells [J].
Davies, Julia R. ;
Kirkham, Sara ;
Svitacheva, Naila ;
Thornton, David J. ;
Carlstedt, Ingemar .
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2007, 39 (10) :1943-1954
[6]   TTF-1 phosphorylation is required for peripheral lung morphogenesis, perinatal survival, and tissue-specific gene expression [J].
deFelice, M ;
Silberschmidt, D ;
DiLauro, R ;
Xu, Y ;
Wert, SE ;
Weaver, TE ;
Bachurski, CJ ;
Clark, JC ;
Whitsett, JA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (37) :35574-35583
[7]   New asthma biomarkers: lessons from murine models of acute and chronic asthma [J].
Di Valentin, Emmanuel ;
Crahay, Celine ;
Garbacki, Nancy ;
Hennuy, Benoit ;
Gueders, Maud ;
Noel, Agnes ;
Foidart, Jean-Michel ;
Grooten, Johan ;
Colige, Alain ;
Piette, Jacques ;
Cataldo, Didier .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2009, 296 (02) :L185-L197
[8]  
Feldman RJ, 2003, CANCER RES, V63, P4626
[9]   Suppressive effect of IL-4 on IL-13-induced genes in mouse lung [J].
Finkelman, FD ;
Yang, MY ;
Perkins, C ;
Schleifer, K ;
Sproles, A ;
Santeliz, J ;
Bernstein, JA ;
Rothenberg, ME ;
Morris, SC ;
Wills-Karp, M .
JOURNAL OF IMMUNOLOGY, 2005, 174 (08) :4630-4638
[10]   Persistent effects induced by IL-13 in the lung [J].
Fulkerson, Patricia C. ;
Fischetti, Christine A. ;
Hassman, Lynn M. ;
Nikolaidis, Nikolaos M. ;
Rothenberg, Marc E. .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2006, 35 (03) :337-346