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R. K. Tittle, R. Sze, A. Ng, R. Nuckels, J. M. Gross; The Role of Chromatin Interacting Proteins Uhrf1 and Dnmt1 in Development of the Zebrafish Lens. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1221.
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The protein Uhrf1 (ubiquitin-like containing PHD and RING finger domains 1) has been implicated in many cellular processes. Among these is the recruitment of Dnmt1 (DNA methyltransferase protein 1) to hemimethylated DNA, which results in maintenance of cytosine methylation patterns after replication. Because genes with methylated promoters are less likely to be transcribed, this is a method of maintaining epigenetic transcriptional silencing in specific cell types. uhrf1 is expressed in proliferating tissues of the zebrafish embryo, including the retina, and zebrafish lacking uhrf1 have severe lens abnormalities which manifest by 4 days post fertilization. In the present study, we sought to determine the cellular mechanisms responsible for this phenotype.
Two lines of zebrafish that are effective null mutants for uhrf1 and dnmt1, respectively, have been utilized in this study. Mutant fish lens formation has been assayed throughout embryogenesis using histological and immunohistochemical techniques. Additionally, in situ hybridation has been performed to identify relevant mRNA distribution in wild type fish, and biochemical techniques have examined the interaction of Uhrf1 and Dnmt1 in vivo.
Lenses of uhrf1 mutant fish display many abnormalities, including disorganized and unraveled secondary fiber cells and epithelial cell ectopic proliferation. In many cases, the lenses have ruptured through the lens capsule. At the time this phenotype becomes apparent, uhrf1 is expressed in the ciliary marginal zones of the retina and not in the lens itself. Lens abnormalities in uhrf1 mutants are phenocopied both in dnmt1 mutants and in uhrf1/dnmt1 double mutants, and the expression pattern of dnmt1 is nearly identical to that of uhrf1.
Our results support the model that the disrupted lens phenotype found in uhrf1 mutants is due to a lack of interaction with the Dnmt1 protein. We hypothesize that formation and maintenance of the zebrafish lens requires epigenetic silencing of genes expressed within the ciliary marginal zone of the retina.
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