Notch signaling controls the balance of ciliated and secretory cell fates in developing airways

被引:282
作者
Tsao, Po-Nien [1 ,3 ]
Vasconcelos, Michelle [1 ,4 ]
Izvolsky, Konstantin I. [1 ]
Qian, Jun [1 ]
Lu, Jining [1 ]
Cardoso, Wellington V. [1 ,2 ]
机构
[1] Boston Univ, Sch Med, Dept Med, Ctr Pulm, Boston, MA 02118 USA
[2] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA
[3] Natl Taiwan Univ, Coll Med, Dept Pediat, Natl Taiwan Univ Hosp, Taipei, Taiwan
[4] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Dev Biol, BR-05508900 Sao Paulo, Brazil
来源
DEVELOPMENT | 2009年 / 136卷 / 13期
关键词
Notch; Pofut1; Rbpjk (Rbpj); Cell fate; Lung development; Airway differentiation; Ciliated cell; Clara cell; Neuroendocrine cell; HAMSTER TRACHEAL EPITHELIUM; LUNG DEVELOPMENT; DIFFERENTIATION; MOUSE; EXPRESSION; SOX2; GENE; PROLIFERATION; O-FUCOSYL-TRANSFERASE-1; MORPHOGENESIS;
D O I
10.1242/dev.034884
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Although there is accumulated evidence of a role for Notch in the developing lung, it is still unclear how disruption of Notch signaling affects lung progenitor cell fate and differentiation events in the airway epithelium. To address this issue, we inactivated Notch signaling conditionally in the endoderm using a Shh-Cre deleter mouse line and mice carrying floxed alleles of the Pofut1 gene, which encodes an O-fucosyltransferase essential for Notch-ligand binding. We also took the same conditional approach to inactivate expression of Rbpjk, which encodes the transcriptional effector of canonical Notch signaling. Strikingly, these mutants showed an almost identical lung phenotype characterized by an absence of secretory Clara cells without evidence of cell death, and showed airways populated essentially by ciliated cells, with an increase in neuroendocrine cells. This phenotype could be further replicated in cultured wild-type lungs by disrupting Notch signaling with a gamma-secretase inhibitor. Our data suggest that Notch acts when commitment to a ciliated or non-ciliated cell fate occurs in proximal progenitors, silencing the ciliated program in the cells that will continue to expand and differentiate into secretory cells. This mechanism may be crucial to define the balance of differentiated cell profiles in different generations of the developing airways. It might also be relevant to mediate the metaplastic changes in the respiratory epithelium that occur in pathological conditions, such as asthma and chronic obstructive pulmonary disease.
引用
收藏
页码:2297 / 2307
页数:11
相关论文
共 62 条
[41]   T1α, a lung type I cell differentiation gene, is required for normal lung cell proliferation and alveolus formation at birth [J].
Ramirez, MI ;
Millien, G ;
Hinds, A ;
Cao, YX ;
Seldin, DC ;
Williams, MC .
DEVELOPMENTAL BIOLOGY, 2003, 256 (01) :61-72
[42]   Lung development and repair: Contribution of the ciliated lineage [J].
Rawlins, Emma L. ;
Ostrowski, Lawrence E. ;
Randell, Scott H. ;
Hogan, Brigid L. M. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (02) :410-417
[43]   Epithelial stem cells of the lung: privileged few or opportunities for many? [J].
Rawlins, Emma L. ;
Hogan, Brigid L. M. .
DEVELOPMENT, 2006, 133 (13) :2455-2465
[44]   Secretoglobins SCGB3A1 and SCGB3A2 define secretory cell subsets in mouse and human airways [J].
Reynolds, SD ;
Reynolds, PR ;
Pryhuber, GS ;
Finder, JD ;
Stripp, BR .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2002, 166 (11) :1498-1509
[45]   The airway goblet cell [J].
Rogers, DF .
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2003, 35 (01) :1-6
[46]   The O-fucosyltransferase O-fut1 is an extracellular component that is essential for the constitutive endocytic trafficking of Notch in Drosophila [J].
Sasamura, Takeshi ;
Ishikawa, Hiroyuki O. ;
Sasaki, Nobuo ;
Higashi, Syunsuke ;
Kanai, Maiko ;
Nakao, Shiho ;
Ayukawa, Tomonori ;
Aigaki, Toshiro ;
Noda, Katsuhisa ;
Miyoshi, Eiji ;
Taniguchi, Naoyuki ;
Matsuno, Kenji .
DEVELOPMENT, 2007, 134 (07) :1347-1356
[47]   Notch-1 regulates pulmonary neuroendocrine cell differentiation in cell lines and in transgenic mice [J].
Shan, Lin ;
Aster, Jon C. ;
Sklar, Jeffrey ;
Sunday, Mary E. .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2007, 292 (02) :L500-L509
[48]   Canonical Notch signaling is dispensable for early cell fate specifications in mammals [J].
Shi, SL ;
Stahl, M ;
Lu, LC ;
Stanley, P .
MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (21) :9503-9508
[49]   Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways [J].
Shi, SL ;
Stanley, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (09) :5234-5239
[50]   Clara cell secretory protein deficiency alters Clara cell secretory apparatus and the protein composition of airway lining fluid [J].
Stripp, BR ;
Reynolds, SD ;
Boe, IM ;
Lund, J ;
Power, JHT ;
Coppens, JT ;
Wong, V ;
Reynolds, PR ;
Plopper, CG .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2002, 27 (02) :170-178