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Chia-Yang Liu, Yujin Zhang, Tien Le, Nadean L. Brown, Warren S. Pear, Winston W. Kao; Role of Canonical Notch Signaling in Ocular Surface Morphogenesis and Disease. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2699. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Conjunctival goblet cells synthesize mainly mucins and other glycogens to lubricate mucus ocular surface tissues, essential for normal vision. Loss of goblet cells can be manifested in ocular surface diseases such as dry eye. Notch signaling has been associated with goblet cell differentiation in guts and lung, but its function in ocular surface remains elusive.
To test whether Notch de-regulation can have strong impact on ocular glands morphogenesis, conjunctival goblet cell differentiation and manifest dry eye, we conditionally inactivate canonical Notch pathway by expressing dominant negative mastermind-like-1 (dn-MAML1) in ocular surface epithelium (OSdn-MAML1) in triple transgenic mice K14-rtTA/tetO-Cre/Rosaloxp-stop-loxp-dn-MAML1 subjected to doxycycline (Dox) induction in different time frame during or following development.
Dox-induction of OSdn-MAML1 from embryonic (E) day 12.5 to postnatal (P) days 6, 9, 12, and 21 caused hyperplasia and failed to generate any goblet cells. Likewise, Dox-induction of OSdn-MAML1 in adult mice (from P90 to P180) completely eliminated the goblet cells from conjunctiva. Expression of OSdn-MAML1 did not trigger cell apoptosis, but increased BrdU incorporation. Immunostaining revealed that OSdn-MAML1 induced CD45+ leukocyte infiltration into conjunctival stroma. Krt1.12 expression level decreased but epidermal keratin Krt1.10 was detected in the cornea. In addition, conditional knock-out of Jagged1, Notch1, and RBPJ floxed alleles, respectively, using Le-Cre mouse driver recapitulated OSdn-MAML1 phenotypes in conjunctiva and exihibited lacrimal gland degeneration and Meibomian gland hyperplasia. Interestingly, however, both Le-Cre/Notch2flox/flox and Le-Cre/DLL1flox/flox mice are normal in ocular surface morphogenesis. These data suggested that canonical Notch1 (but not Notch2) signaling stimulated by Jagged1 (but not Dll1) plays a pivotal role in ocular glands morphogenesis and conjunctival goblet differentiation during development. The canonical Notch signal pathway is also indispensible for the maintenance of goblet cells in the adult to ensure ocular surface homeostasis.
Loss of Notch signaling results in degeneration of lacrimal glands, hyperplasia of Meibomian gland, and loss of goblet cells, which lead to ocular surface metaplasia and severe dry eye. These mouse strains may serve as novel animal model to study the pathogenesis of Notch de-regulation in ocular surface diseases.
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