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Dennis M. Maddox, Wanda L. Hicks, Douglas Vollrath, Matthew M. LaVail, Jürgen K. Naggert, Patsy M. Nishina; An ENU-Induced Mutation in the Mertk Gene (Mertknmf12 ) Leads to a Slow Form of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(7):4703-4709. https://doi.org/10.1167/iovs.10-7077.
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To determine the basis and to characterize the phenotype of a chemically induced mutation in a mouse model of retinal degeneration.
Screening by indirect ophthalmoscopy identified a line of N-ethyl-N-nitrosourea (ENU) mutagenized mice demonstrating retinal patches. Longitudinal studies of retinal histologic sections showed photoreceptors in the peripheral retina undergoing slow, progressive degeneration. The mutation was named neuroscience mutagenesis facility 12 (nmf12), and mapping localized the critical region to Chromosome 2.
Sequencing of nmf12 DNA revealed a point mutation in the c-mer tyrosine kinase gene, designated Mertknmf12 . We detected elevated levels of tumor necrosis factor (Tnf, previously Tnfa) in retinas of Mertknmf12 homozygotes relative to wild-type controls and investigated whether the increase of TNF, an inflammatory cytokine produced by macrophages/monocytes that signals intracellularly to cause necrosis or apoptosis, could underlie the retinal degeneration observed in Mertknmf12 homozygotes. Mertknmf12 homozygous mice were mated to mice lacking the entire Tnf gene and partial coding sequences of the Lta (Tnfb) and Ltb (Tnfc) genes. 2 B6.129P2-Ltb/Tnf/Ltatm1Dvk /J homozygotes did not exhibit a retinal degeneration phenotype and will, hereafter, be referred to as Tnfabc −/− mice. Surprisingly, mice homozygous for both the Mertknmf12 and the Ltb/Tnf/Ltatm1Dvk allele (Tnfabc −/−) demonstrated an increase in the rate of retinal degeneration.
These findings illustrate that a mutation in the Mertk gene leads to a significantly slower progressive retinal degeneration compared with other alleles of Mertk. These results demonstrate that TNF family members play a role in protecting photoreceptors of Mertknmf12 homozygotes from cell death.
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