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Krushangi Patel, Igor Nasonkin, Jerome Roger, Kevin Lazo, Dustin Hambright, Rudolf Jaenisch, Milan Jamrich, Anand Swaroop; The Role of Dnmt1 in Retinal Differentiation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5982.
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© ARVO (1962-2015); The Authors (2016-present)
Methylation is generally associated with repression of gene expression (Razin 1991). Conditional ablation of exons 4 and 5 in Dnmt1 2lox mouse model is expected to cause demethylation (Jackson-Grusby et al. 2001) and as a result derepression of the genetic program in the developing neural retina (nr) leading to premature gene expression resulting in aberrant maturation of nr cells including photoreceptors (PRs). The goal of this project is to delineate the role of DNA Methyltransferase-1 (Dnmt1) in retinal development.
We generated Dnmt12lox, Six3Cre mice to study the effect of early demethylation on nr development. Using histology and immunohistochemistry (IHC), we examined the changes in nr development in mutant mice at several stages of differentiation: P0.5, P10.5, 3wk, 6 wk, and 3-4 months.
We observed the early and severe degeneration of the central retina in the mutant retinas by postnatal day P10.5, while peripheral retinal changes were only subtle. Pathology was observed in the peripheral retina only by 3-4 months. There is further indication of uneven changes in mutants along the dorso-vental nr axis. We also detected a significant loss of cones in mutant retina, as evidenced by Cone Arrestin (CAR) and Peanut Agglutinin Lectin (PNA) IHC.
DNMT1-mediated DNA methylation and DNMT1 function are crucial for retinal development and cell survival.
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