Abstract
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-Chr3A/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.
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Acknowledgments
The authors thank Zhen Zhang for development and technical support of E-mouseLab, Katie Clowers and Zak Lemmon for feedback and assistance with R/qtl, and the University of Wisconsin-Madison Genetics Confocal Facility for the use of the confocal microscope. This work was supported by a grant from the National Institutes of Health (NIH R01EY016108) and a core Grant to Waisman Center (NIH P30HD03352). Support for S.V.K-S was partially provided by the NIH predoctoral training program in Genetics (NIH 5T32GM07133).
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Kawakami-Schulz, S.V., Sattler, S.G., Doebley, AL. et al. Genetic modification of corneal neovascularization in Dstn corn1 mice. Mamm Genome 24, 349–357 (2013). https://doi.org/10.1007/s00335-013-9468-9
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DOI: https://doi.org/10.1007/s00335-013-9468-9