Wakayama symposium: role of canonical Notch signaling in conjucntival goblet cell differentiation and dry eye syndrome
© Liu. 2015
Published: 17 December 2015
This review summarizes a recent finding regarding the intrinsic canonical Notch signaling pathway in regulating normal ocular surface morphogenesis and its role in the pathogenesis of goblet cell deficiency-associated keratoconjunctivitis sicca (KCS, or dry eye). Specifically, we used novel transgenic mice to investigate the mechanism of how the Notch1 activation may serve as the upstream control of expression of transcription factors Krüppel-like factors 4 or 5 (Klf4 or Klf5) which in turn controls goblet cell differentiation and activates mucin 5/ac synthesis during ocular surface morphogenesis.
Ocular surface goblet cells are polarized epithelial cells scattered along the conjunctival epithelium in which their numbers in bulbar (or ocular) conjunctiva at the fornix area are much more abundant than those in palpebral (or tarsal) conjunctiva. Conjunctival goblet cell is the major cell type that synthesizes and secrets mucins for the maintenance of ocular surface integrity. Lack of mucins in tear film due to goblet cells abnormality causes dry eye syndrome (DES) and affects millions of people’s vision and life [1–3]. The lack of knowledge regarding the regulatory mechanisms by which conjunctival epithelial cells differentiate to form goblet cells hampers the development of treatment regimens for DES.
The cellular mechanism underlying goblet cell formation and related pathogenesis in the ocular surface epithelia is poorly understood. A recent report showed that members of the canonical Notch signaling pathway i.e., Notch1, Notch2, Notch3, Jagged1, Dll1, were significantly down-regulated in dry eye as compared to the non-dry eye conjunctival epithelia . This result suggested that Notch deregulation played an important role in the pathogenesis of human dry eye syndrome. Nevertheless, the specific function of canonical Notch signaling pathway in ocular surface goblet cell fate determination has not been well documented or explored in vivo. Therefore, it is important to understand the molecular basis of how epithelial phenotypes of nonkeratinization and mucin expression are modulated by Notch signaling to endow the mucous ocular surface with sufficient moisture that is essential to maintain the integrity and health of the corneal and conjunctival surface.
Canonical Notch signaling
Notch signaling is a central mediator of short-range inter-cellular communication in metazoans [5, 6]. It regulates cell fate decision and plays critical roles in controlling goblet cell differentiation in the gut epithelium . Moreover, Notch activation has been postulated to contribute in the maintenance of corneal [8–11] and conjunctival [12, 13] phenotypes. The Notch receptor exists at the cell surface as a proteolytically cleaved heterodimer consisting of a large ectodomain and a membrane-tethered intracellular domain. Ligands of the Delta-like (DLL1, DLL3, DLL4) and Jagged (JAG1 and JAG2) families interact with receptors of Notch family (NOTCH1-4) on an adjacent cell. The ligand-receptor interaction induces further proteolytic cleavages of the Notch that release the Notch intracellular domain (NICD) from the cell membrane. The NICD translocates into the nucleus, where it forms a complex with the recombination signal binding protein for immunoglobulin kappa J region (RBP-Jκ) protein, displacing a histone deacetylase (HDAc)-co-repressor (CoR) complex from the RBP-Jκ protein. Components of an activation complex, i.e., transcriptional co-activators mastermind-like protein 1 (MAML1) and histone acetyltransferase (HAT) p300, are recruited to the NICD-RBP-Jκ complex, leading to the transcriptional activation of Notch target genes such as Hes1 (hairy and enchancer of split-1)/Hey1 (Hairy/enhancer-of-split related with YRPW motif 1) and others .
Findings in transgenic mouse model
K14-rtTA (K14-rt): Keratin 14-promoter-driven reverse tetracycline trans-activator ,
tet-O-Cre (TC): Cre recombinase under the control of a tetracycline-responsive promoter element (TRE; tet-O) , and
Rosa LSL-dnMAML1 : a fusion cDNA cassette LSL-dnMAML1 consisting of two LoxP (L) sites flanked stop (S) sequence followed by a dominant negative MAML1 under the control of the mouse Rosa 26 gene locus .
All the mice were bred at the Animal Facility of the University of Cincinnati Medical Center. Experimental procedures for handling the mice were approved by the Institutional Animal Care and Use Committee, University of Cincinnati/College of Medicine.
This work was supported by grants from NIH/NEI RO1 EY21501, Research Prevent Blindness, Ohio Lions Foundation for Eye Research.
This article has been published as part of BMC Ophthalmology Volume 15 Supplement 1, 2015: Proceedings of the 2nd Ocular Cell Biology Symposium at Wakayama. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcophthalmol/supplements.
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