title: Mastermind-like transcriptional co-activator-mediated Notch signaling is indispensable for maintaining conjunctival epithelial identity.
abstract: 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.affiliation: Edith J. Crawley Vision Research Center/Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267,  USA.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Oliver
authors.initials: O
authors.lastname: Lam
authors.forename: Minh-Thanh T
authors.initials: MT
authors.lastname: Nguyen
authors.forename: Gracia
authors.initials: G
authors.lastname: Ng
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
authors.forename: Walden
authors.initials: W
authors.lastname: Ai
authors.forename: I-Jong
authors.initials: IJ
authors.lastname: Wang
authors.forename: Winston W-Y
authors.initials: WW
authors.lastname: Kao
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Liu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003228:Conjunctiva / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D003315:Cornea / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D019573:Epithelium, Corneal / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D007765:Lacrimal Apparatus / Q000378:metabolism / Q000473:pathology; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C000715468:Klf4 protein, mouse; C118391:Klf5 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C486455:Maml1 protein, mouse; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; C497762:Notch1 protein, mouse; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D014157:Transcription Factors