Genetic modification of corneal neovascularization in Dstn (corn1) mice.
Mutations in the gene for destrin (Dstn), an actin depolymerizing factor, lead to corneal abnormalities in mice. A null mutation in Dstn, termed Dstn (corn1) , isolated and maintained in the A.BY background (A.BY Dstn (corn1) ), results in corneal epithelial hyperproliferation, inflammation, and neovascularization. We previously reported that neovascularization in the cornea of Dstn (corn1) mice on the C57BL/6 background (B6.A.BY-Dstn (corn1) ) is significantly reduced when compared to A.BY Dstn (corn1) mice, suggesting the existence of genetic modifier(s). The purpose of this study is to identify the genetic basis of the difference in corneal neovascularization between A.BY Dstn (corn1) and B6.A.BY-Dstn (corn1) mice. We generated N2 mice for a whole-genome scan by backcrossing F1 progeny (A.BY Dstn (corn1) × B6.A.BY-Dstn (corn1) ) to B6.A.BY-Dstn (corn1) mice. N2 progeny were quantitatively phenotyped for the extent of corneal neovascularization and genotyped for markers across the mouse genome. We identified significant association of variability in corneal neovascularization with a locus on chromosome 3 (Chr3). The validity of the identified quantitative trait locus (QTL) was tested using B6 consomic mice carrying Chr3 from A/J mice. Dstn (corn1) mice from F1 and F2 intercrosses (B6.A.BY-Dstn (corn1)  × C57BL/6J-Chr3(A/J)/NaJ) were phenotyped for the extent of corneal neovascularization. This analysis showed that mice carrying the A/J allele at the QTL show significantly increased neovascularization. Our results indicate the existence of a modifier that genetically interacts with the Dstn gene. This modifier demonstrates allelic differences between C57BL6 and A.BY or A/J. The modifier is sufficient to increase neovascularization in Dstn (corn1) mice.
Department of Medical Genetics, University of Wisconsin, Madison, WI, 53706, USA.
Sharolyn V
SV
Kawakami-Schulz
Shannon G
SG
Sattler
Anna-Lisa
AL
Doebley
Akihiro
A
Ikeda
Sakae
S
Ikeda
D000818:Animals; D016510:Corneal Neovascularization / Q000235:genetics*; D051345:Destrin / Q000235:genetics* / Q000378:metabolism; D004843:Epistasis, Genetic; D056726:Genetic Association Studies; D008126:Lod Score; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D040641:Quantitative Trait Loci
D051345:Destrin; C495825:Dstn protein, mouse