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Joel Dietz, Shuang Huang, Brian Yandell, James Ver Hoeve, Robert Nickells; Narrowing of the Rgcs1 QTL that Dominantly Influences Ganglion Cell Death After Optic Nerve Crush In Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4515.
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© ARVO (1962-2015); The Authors (2016-present)
Previously we mapped a QTL affecting ganglion cell death after optic nerve crush in mice, located between 34 and 39 cM on chromosome 5 (Locus Rgcs1). This region conferred susceptibility to crush in BALB/cByJ mice and resistance in DBA/2J mice. This study reports further refinement of the Rgcs1 locus to 1 million base pairs and evaluation of a DBA/2J.BALBRgcs1 substrain of mice.
Chr5.loc34-loc59 was fine mapped with 43 informative TaqMan SNPs (Applied Biosystems) using an ABI 7300 Real Time PCR machine. Mice used for mapping were a population of 200 F2 mice that had undergone optic nerve crush at 8 weeks of age and were euthanized for analysis 2 weeks later. A congenic substrain of DBA/2J animals carrying the BALBRgcs1 allele was created by 10 successive backcrosses of DBA/2J.BALBRgcs1 animals with pure-bred DBA/2J mice. The ganglion cell marker gene, Fem1cRosa3, was also congenically bred onto this background. Crush-induced expression changes in candidate genes within the narrowed Rgcs1 locus were evaluated from retinas and optic nerves of both parental strains by qPCR.
SNP fine-mapping of F2 mice revealed a significant QTL (LOD 6.85) between 76.7 and 77.8 megabases on chromosome 5. This interval contains 26 known or putative genes and 3 pseudogenes. Of these, 19 were successfully amplified from either retina or optic nerve tissues, and only 1 (Spink2) exhibited an increase in expression in response to optic nerve crush. Overall, however, latent transcript levels were selectively higher for most of the genes in this, versus other loci, in BALB/cByJ derived-tissues. Preliminary crush studies with DBA/2J.BALBRgcs1 mice indicate that the BALB allele confers susceptibility to crush in DBA/2J mice. Glaucoma studies are ongoing.
Susceptibility to optic nerve crush is affected by a gene residing between Chr5 76.7 and 77.8 megabases. Based on expression studies, Spink2 may be an interesting candidate gene for further study.
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