Document Detail


Mastermind-like transcriptional co-activator-mediated Notch signaling is indispensable for maintaining conjunctival epithelial identity.
MedLine Citation:
PMID:  23293291     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Conjunctival goblet cells primarily synthesize mucins to lubricate the ocular surface, which is essential for normal vision. Notch signaling has been known to associate with goblet cell differentiation in intestinal and respiratory tracts, but its function in ocular surface has yet to be fully characterized. Herein, we demonstrate that conditional inhibition of canonical Notch signaling by expressing dominant negative mastermind-like 1 (dnMaml1) in ocular surface epithelia resulted in complete suppression of goblet cell differentiation during and subsequent to development. When compared with the ocular surface of wild-type mice (OS(Wt)), expression of dnMaml1 at the ocular surface (OS(dnMaml1)) caused conjunctival epithelial hyperplasia, aberrant desquamation, failure of Mucin 5ac (Muc5ac) synthesis, subconjunctival inflammation and epidermal metaplasia in cornea. In addition, conditional deletion of Notch1 from the ocular surface epithelia partially recapitulated OS(dnMaml1) phenotypes. We have demonstrated that N1-ICD (Notch1 intracellular domain) transactivated the mouse Krüppel-like factor 4 (Klf) promoter and that Klf4 directly bound to and significantly potentiated the Muc5ac promoter. By contrast, OS(dnMaml1) dampened Klf4 and Klf5 expression, and diminished Muc5ac synthesis. Collectively, these findings indicated that Maml-mediated Notch signaling plays a pivotal role in the initiation and maintenance of goblet cell differentiation for normal ocular surface morphogenesis and homeostasis through regulation of Klf4 and Klf5.
Authors:
Yujin Zhang; Oliver Lam; Minh-Thanh T Nguyen; Gracia Ng; Warren S Pear; Walden Ai; I-Jong Wang; Winston W-Y Kao; Chia-Yang Liu
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  140     ISSN:  1477-9129     ISO Abbreviation:  Development     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-07     Completed Date:  2013-03-07     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  England    
Other Details:
Languages:  eng     Pagination:  594-605     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Differentiation
Cell Proliferation
Conjunctiva / embryology,  metabolism*,  pathology
Cornea / embryology,  metabolism,  pathology
Epithelium, Corneal / embryology,  metabolism,  pathology*
Gene Deletion
Gene Expression Regulation, Developmental
Goblet Cells / metabolism,  pathology
Hyperplasia / genetics,  pathology
Inflammation / genetics,  metabolism,  pathology
Kruppel-Like Transcription Factors / genetics,  metabolism
Lacrimal Apparatus / metabolism,  pathology
Metaplasia / metabolism,  pathology
Mice
Mice, Transgenic
Mucin 5AC / genetics,  metabolism
Nuclear Proteins / genetics,  metabolism
Phenotype
Promoter Regions, Genetic
Receptor, Notch1 / genetics,  metabolism*
Signal Transduction*
Transcription Factors / genetics,  metabolism
Transcriptional Activation*
Grant Support
ID/Acronym/Agency:
EY13755/EY/NEI NIH HHS; KO1 DK069489/DK/NIDDK NIH HHS; P30 CA016520/CA/NCI NIH HHS; R01 EY021501/EY/NEI NIH HHS; R01 EY21501/EY/NEI NIH HHS
Chemical
Reg. No./Substance:
0/GKLF protein; 0/Klf5 protein, mouse; 0/Kruppel-Like Transcription Factors; 0/Maml1 protein, mouse; 0/Muc5ac protein, mouse; 0/Mucin 5AC; 0/Notch1 protein, mouse; 0/Nuclear Proteins; 0/Receptor, Notch1; 0/Transcription Factors
Comments/Corrections

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