Document Detail

NOTCH1 is required for regeneration of Clara cells during repair of airway injury.
MedLine Citation:
PMID:  22331706     Owner:  NLM     Status:  MEDLINE    
The airways of the mammalian lung are lined with highly specialized epithelial cell types that are the targets of airborne toxicants and injury. Notch signaling plays an important role in the ontogeny of airway epithelial cells, but its contributions to recruitment, expansion or differentiation of resident progenitor/stem cells, and repair and re-establishment of the normal composition of airway epithelium following injury have not been addressed. In this study, the role of a specific Notch receptor, Notch1, was investigated by targeted inactivation in the embryonic lung epithelium using the epithelial-specific Gata5-Cre driver line. Notch1-deficient mice are viable without discernible defects in pulmonary epithelial cell-fate determination and differentiation. However, in an experimental model of airway injury, activity of Notch1 is found to be required for normal repair of the airway epithelium. Absence of Notch1 reduced the ability of a population of cells distinguished by expression of PGP9.5, otherwise a marker of pulmonary neuroendocrine cells, which appears to serve as a reservoir for regeneration of Clara cells. Hairy/enhancer of split-5 (Hes5) and paired-box-containing gene 6 (Pax6) were found to be downstream targets of Notch1. Both Hes5 and Pax6 expressions were significantly increased in association with Clara cell regeneration in wild-type lungs. Ablation of Notch1 reduced Hes5 and Pax6 and inhibited airway epithelial repair. Thus, although dispensable in developmental ontogeny of airway epithelial cells, normal activity of Notch1 is required for repair of the airway epithelium. The signaling pathway by which Notch1 regulates the repair process includes stimulation of Hes5 and Pax6 gene expression.
Yiming Xing; Aimin Li; Zea Borok; Changgong Li; Parviz Minoo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Stem cells (Dayton, Ohio)     Volume:  30     ISSN:  1549-4918     ISO Abbreviation:  Stem Cells     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-04-10     Completed Date:  2012-07-30     Revised Date:  2014-05-14    
Medline Journal Info:
Nlm Unique ID:  9304532     Medline TA:  Stem Cells     Country:  United States    
Other Details:
Languages:  eng     Pagination:  946-55     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 AlphaMed Press.
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MeSH Terms
Basic Helix-Loop-Helix Transcription Factors / biosynthesis,  genetics
Eye Proteins / biosynthesis,  genetics
Gene Expression Regulation / genetics
Homeodomain Proteins / biosynthesis,  genetics
Lung Injury / genetics,  metabolism*,  pathology
Mice, Knockout
Paired Box Transcription Factors / biosynthesis,  genetics
Receptor, Notch1 / genetics,  metabolism*
Repressor Proteins / biosynthesis,  genetics
Respiratory Mucosa / injuries,  metabolism*,  pathology
Signal Transduction*
Ubiquitin Thiolesterase / biosynthesis,  genetics
Grant Support
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/Eye Proteins; 0/Hes5 protein, mouse; 0/Homeodomain Proteins; 0/Notch1 protein, mouse; 0/PAX6 protein; 0/Paired Box Transcription Factors; 0/Receptor, Notch1; 0/Repressor Proteins; EC 3.1.2.-/PGP9.5 protein, mouse; EC Thiolesterase
Erratum In:
Stem Cells. 2012 Jul;30(7):1579

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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