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S. S. Saravanamuthu, T. Le, N. L. Brown, C. Y. Gao, T. Gridley, P. S. Zelenka; Conditional Deletion of Notch2 in Lens. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2621.
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© ARVO (1962-2015); The Authors (2016-present)
Notch signaling is highly conserved and regulates transcription during diverse developmental and physiological processes. Key players of canonical notch signaling are Notch receptors (1-4), ligands - Jagged (1,2) and Delta (1,3,4) and CSL (known as CBF-1 or RBP-J in mammals) family transcription factors. Notch intracellular domain (NICD) is released upon ligand binding to the Notch receptor and represents the activated Notch, which translocates to the nucleus and forms a transcriptional complex with CSL to initiate transcription of target genes. Previous studies using conditional gene targeting in mice have shown that disruption of Notch signaling in lens by ablation of RBP-J or Jagged1, led to a block in proliferation of the lens epithelium, leading to aberrant expression of cell cycle regulatory genes, premature differentiation, and a dysgenic lens. Our own previous studies demonstrated a role for Jagged1-Notch2 signaling in secondary fiber cell differentiation establishing distinct dual roles for canonical Notch signaling in the lens proliferation and differentiation. However, relative contributions of the two Notch receptors Notch1 and 2 expressed in the lens, is still unclear. This work investigates Notch2 receptor mediated signaling in lens differentiation and development by generating and characterizing the ocular phenotypes of lens specific conditional knockouts of Notch2 receptor (Notch2CN) in mice.
Notch2CN mice were generated using Cre-Lox approach by crossing mice carrying Le-Cre driver (Ashrey-Padan et al., 2000) and Notch2 flox/flox (McCright et al., 2006). The ocular phenotypes were analyzed using histology.
Notch2CN mice were microphthalmic, lenses lacked epithelial cells and fiber cells were disorganized and failed to elongate normally. Cataract was of common occurrence in Notch2CN mice as was the fusion of lens tissue with iris. Pupillary opening was smaller or non-existent in some Notch2 CN.
Notch2 receptor mediated signaling is critical for canonical Notch signaling in the lens. The severity of the lens defects in the Notch2CN mice appeared to be greater than those of the RBP-JCN and that of Notch1CN mice and comparable to that of Jag1 mice.
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