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Xian-Jie Yang, Kun-Do Rhee, Carrie Y. Zhao, Juehua Yu, Guoping Fan; Function of DNA Methyltransferase 1 (Dnmt1) is Essential for Mouse Retinal Cell Proliferation and Photoreceptor Differentiation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5999.
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© ARVO (1962-2015); The Authors (2016-present)
DNA methylation is essential for regulation of gene expression, X chromosomal inactivation, genomic imprinting, and chromatin modification. Among the three types of DNA methyltransferases, Dnmt1 is involved in maintenance of methylation patterns. Germ line Dnmt1 knockout is embryonic lethal. Brain-specific Dnmt1 conditional knockout (cKO) causes neuronal cell death and promote astroglial differentiation. In this study, we examine the roles of Dnmt1 in the developing mouse retina.
Mice carrying a Dnmt1 loxP allele were crossed with a Chx10-cre transgenic line, which expresses Cre at the onset of retinogenesis. The resulting Dnmt1 cKO mutant retinas were analyzed at various postnatal stages by immunohistochemistry and confocal imaging, western blot analysis, and fluorescence activated cell sorting.
From birth to the adulthood, Dnmt1 cKO retinas show progressive thinning, especially of the outer nuclear layer. At birth, Dnmt1 cKO mutant retinas exhibit a decreased neuroblast layer (ONL). By P3, the mutant retinas show abnormal distribution of progenitor cells. Cell cycle analyses reveal that Dnmt1 deletion results in delayed G1 to S phase entry, and reduced G2/M phase cells. Cell marker labeling shows that most retinal cell types are generated in the Dnmt1 mutant retina, albeit at lower numbers. During the period of photoreceptor differentiation (P3 to P7), significant loss of ONL cells incurs. Photoreceptor fate specification is not affected, as expression of Otx2 among progenitors appears normal. However, postmitotic Crx-positive photoreceptor precursors fail to mature and die quickly at the onset of opsin expression.
Elimination of Dnmt1 function during retinogenesis causes defects in progenitor cell cycle progression and reduced neuronal production. The absence of Dnmt1 activity blocks differentiation of photoreceptor precursor and causes rapid cell death. Therefore, maintaining DNA methylation by Dnmt1 is essential for proper retinal progenitor cell proliferation and photoreceptor differentiation.
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