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J. M. Gross, R. Sze, R. Nuckels; Uhrf1 in the Formation and Maintenance of the Zebrafish Lens. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5029.
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© ARVO (1962-2015); The Authors (2016-present)
Zebrafish have become increasingly useful as animal models of human visual system disorders largely due to the ability to perform genetic screens and rapidly identify the affected loci. In a retrovirus-based insertional mutagenesis screen we identified a recessive mutation disrupting the uhrf1 locus. Uhrf1 (ubiquitin-like containing PHD and RING finger domains 1), also known as NP95 and ICBP90, encodes a chromatin binding protein that has been shown to interact with DNA methyltransferase protein 1 (DNMT1) and histone deactylase 1 (HDAC1) and thereby mediate transcriptional silencing. Uhrf1 mutants display severe defects in lens morphogenesis and maintenance, and here we sought to determine the cellular and molecular underpinnings of these defects.
Histological and ultrastructural characterizations of mutants have been performed throughout embryogenesis. Immunohistochemical studies have assayed lens epithelial cell proliferation, apoptosis and lens fiber differentiation, and embryological and molecular assays have been performed to elucidate the mechanistic underpinnings of the lens defects.
uhrf1 mutants present with severe morphological abnormalities in the lens where most mutant embryos possess lenses that have ruptured through the lens capsule and are ectopically located within the retina. Peripheral lens fibers have degenerated and have unraveled from the core of differentiated fibers such that in many mutants, the entire retina is filled with fiber-like extensions. Lens epithelial cells overproliferate and most of the ectopic cells undergo apoptosis. Paradoxically, uhrf1 is not expressed within the lens; rather, it is expressed in the ciliary marginal zone of the retina. This suggests that the lens defects in uhrf1 mutants are lens non-autonomous and stem from underlying defects in the retina. Lens transplants between wild-type embryos and uhrf1 mutants were performed to test this hypothesis and the results of these transplants support a model in which uhrf1 function is required within the retina for lens formation and maintenance.
Our results demonstrate a critical role for uhrf1 in the retina for lens formation and maintenance. We hypothesize that uhrf1 functions as a modulator of DNA methylation and histone deacetylation that is required for the epigenetic silencing of gene products expressed within the retina.
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