title: Conditional ablation of the Notch2 receptor in the ocular lens.
abstract: Notch signaling is essential for proper lens development, however the specific requirements of individual Notch receptors have not been investigated. Here we report the lens phenotypes of Notch2 conditionally mutant mice, which exhibited severe microphthalmia, reduced pupillary openings, disrupted fiber cell morphology, eventual loss of the anterior epithelium, fiber cell dysgenesis, denucleation defects, and cataracts. Notch2 mutants also had persistent lens stalks as early as E11.5, and aberrant DNA synthesis in the fiber cell compartment by E14.5. Gene expression analyses showed that upon loss of Notch2, there were elevated levels of the cell cycle regulators Cdkn1a (p21Cip1), Ccnd2 (CyclinD2), and Trp63 (p63) that negatively regulates Wnt signaling, plus down-regulation of Cdh1 (E-Cadherin). Removal of Notch2 also resulted in an increased proportion of fiber cells, as was found in Rbpj and Jag1 conditional mutant lenses. However, Notch2 is not required for AEL proliferation, suggesting that a different receptor regulates this process. We found that Notch2 normally blocks lens progenitor cell death. Overall, we conclude that Notch2-mediated signaling regulates lens morphogenesis, apoptosis, cell cycle withdrawal, and secondary fiber cell differentiation.
authors.affiliation: Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Senthil S
authors.initials: SS
authors.lastname: Saravanamuthu
authors.forename: Tien T
authors.initials: TT
authors.lastname: Le
authors.forename: Chun Y
authors.initials: CY
authors.lastname: Gao
authors.forename: Radu I
authors.initials: RI
authors.lastname: Cojocaru
authors.forename: Pushpa
authors.initials: P
authors.lastname: Pandiyan
authors.forename: Chunqiao
authors.initials: C
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Peggy S
authors.initials: PS
authors.lastname: Zelenka
authors.forename: Nadean L
authors.initials: NL
authors.lastname: Brown
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D017403:In Situ Hybridization; D007908:Lens, Crystalline / Q000196:embryology* / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009024:Morphogenesis / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D051883:Receptor, Notch2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017931:DNA Primers; C497765:Notch2 protein, mouse; D051883:Receptor, Notch2