Abstract | PURPOSE: Mutations in destrin (Dstn) cause corneal abnormalities in mice. A null mutation, Dstn(corn1), results in corneal epithelial hyperproliferation, inflammation, and neovascularization in the A.BY background (A.BY Dstn(corn1)). Homozygosity for a point mutation, Dstn(corn1-2J), results in mild thickening of the corneal epithelium but no corneal neovascularization in a C57BL/6 (B6) background (B6 Dstn(corn1-2J)). The goal of this study was to determine whether phenotypic differences are due to allelic differences between Dstn(corn1) and Dstn(corn1-2J), or are the result of genetic background effects. METHODS: We generated two congenic (Cg) mouse lines, B6.Cg-Dstn(corn1) and A.BY.Cg-Dstn(corn1-2J), to compare to the original A.BY Dstn(corn1) and B6 Dstn(corn1-2J) lines. We performed immunohistochemistry to assay F-actin accumulation, neovascularization, proliferation, and inflammation. By western blot analysis we tested the expression of serum response factor (SRF), a known regulator of the Dstn(corn1) phenotype. RESULTS: The Dstn(corn1) mutation leads to neovascularization, hyperproliferation, and inflammation in the cornea of A.BY Dstn(corn1) as well as B6.Cg-Dstn(corn1) mice. We did not observe significant corneal neovascularization or hyperproliferation in either A.BY.Cg-Dstn(corn1-2J) or B6 Dstn(corn1-2J) mice. Actin accumulation, neovascularization, epithelial proliferation and inflammation in B6.Cg-Dstn(corn1) cornea are significantly reduced when compared to A.BY Dstn(corn1)cornea. SRF changes are consistent in Dstn(corn1) mutants, regardless of genetic background. CONCLUSIONS: Differences in the abnormal phenotypes of Dstn mutants result from allelic differences between Dstn(corn1) and Dstn(corn1-2J) . Moreover, phenotypes of Dstn(corn1) mice are modified by genetic background, suggesting the existence of genetic modifiers. Protein analysis suggests that a genetic modifier affects phenotypic severity functionally downstream from or in a pathway independent from SRF. These data demonstrate that natural genetic variation affects phenotypic severity in Dstn(corn1) mice.
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Authors | Sharolyn V Kawakami-Schulz, Angela M Verdoni, Shannon G Sattler, Akihiro Ikeda, Sakae Ikeda |
Journal | Molecular vision
(Mol Vis)
Vol. 18
Pg. 606-16
( 2012)
ISSN: 1090-0535 [Electronic] United States |
PMID | 22419854
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Actins
- Destrin
- Dstn protein, mouse
- Protein Kinases
- serum response factor kinase
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Topics |
- Actins
(genetics, metabolism)
- Alleles
- Animals
- Cornea
(blood supply, metabolism, pathology)
- Corneal Neovascularization
(genetics, metabolism)
- Destrin
(genetics, metabolism)
- Founder Effect
- Gene Expression
- Genetic Association Studies
- Genetic Predisposition to Disease
- Genotype
- Mice
- Mice, Transgenic
- Mutation
- Phenotype
- Protein Kinases
(genetics, metabolism)
- Severity of Illness Index
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