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Spink2 modulates apoptotic susceptibility and is a candidate gene in the Rgcs1 QTL that affects retinal ganglion cell death after optic nerve damage.

Dietz JA, Maes ME, Huang S, Yandell BS, Schlamp CL, Montgomery AD, Allingham RR, Hauser MA, Nickells RW - PLoS ONE (2014)

Bottom Line: In this region, a single gene (Spink2) is the most likely candidate for this effect.This gene is also polymorphic between resistant and susceptible strains, containing a single conserved amino acid change (threonine to serine) and a 220 bp deletion in intron 1 that may quantitatively alter endogenous expression levels between strains.Overexpression of the different variants of Spink2 in D407 tissue culture cells also increases their susceptibility to the apoptosis-inducing agent staurosporine in a manner consistent with the differential susceptibility between the DBA/2J and BALB/cByJ strains.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States of America.

ABSTRACT
The Rgcs1 quantitative trait locus, on mouse chromosome 5, influences susceptibility of retinal ganglion cells to acute damage of the optic nerve. Normally resistant mice (DBA/2J) congenic for the susceptible allele from BALB/cByJ mice exhibit susceptibility to ganglion cells, not only in acute optic nerve crush, but also to chronic inherited glaucoma that is characteristic of the DBA/2J strain as they age. SNP mapping of this QTL has narrowed the region of interest to 1 Mb. In this region, a single gene (Spink2) is the most likely candidate for this effect. Spink2 is expressed in retinal ganglion cells and is increased after optic nerve damage. This gene is also polymorphic between resistant and susceptible strains, containing a single conserved amino acid change (threonine to serine) and a 220 bp deletion in intron 1 that may quantitatively alter endogenous expression levels between strains. Overexpression of the different variants of Spink2 in D407 tissue culture cells also increases their susceptibility to the apoptosis-inducing agent staurosporine in a manner consistent with the differential susceptibility between the DBA/2J and BALB/cByJ strains.

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DBA/2J.BALBRgcs1 substrain mice exhibit a susceptible phenotype after optic nerve crush.Bar graph showing cell loss after optic nerve crush (mean ± sem) in DBA/2J mice carrying the BALB/cByJ Rgcs1 allele (C). Mice with the CC allele exhibit a significantly greater percentage of cell loss in the ganglion cell layer than either DD or DC mice (P = 0.024, CC compared to the DD and DC animals combined). This difference in phenotype mimics the difference between purebred DBA/2J mice compared to purebred BALB/cByJ mice [10]. A minimum of 20 mice was assayed per group.
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pone-0093564-g001: DBA/2J.BALBRgcs1 substrain mice exhibit a susceptible phenotype after optic nerve crush.Bar graph showing cell loss after optic nerve crush (mean ± sem) in DBA/2J mice carrying the BALB/cByJ Rgcs1 allele (C). Mice with the CC allele exhibit a significantly greater percentage of cell loss in the ganglion cell layer than either DD or DC mice (P = 0.024, CC compared to the DD and DC animals combined). This difference in phenotype mimics the difference between purebred DBA/2J mice compared to purebred BALB/cByJ mice [10]. A minimum of 20 mice was assayed per group.

Mentions: The Rgcs1 QTL from BALB/cByJ mice was identified as a recessive allele that was linked to greater cell loss after optic nerve crush in these mice. To test further the ability of this region to modulate the cell death phenotype in the resistant DBA/2J strain, the region of chromosome 5 flanked by microsatellite markers D5Mit254 (34 cM) and D5Mit338 (59 cM) was bred onto the DBA/2J background through 10 successive generations. Substrain mice, heterozygous and homozygous for the BALB/cByJ locus were then subjected to the optic nerve crush procedure at 8 weeks of age and compared to pure bred DBA/2J animals. DBA/2J mice exhibit retinal ganglion cell loss after optic nerve damage [1], but the rate and amount of cell loss is less than other strains [10], which is why they were classified as the “resistant” strain. Consistent with previous studies, mice homozygous for the BALB/cByJ Rgcs1 region exhibited significantly more cell loss (to levels similar to pure bred BALB/cByJ mice – data not shown) compared to mice carrying the DBA/2J allele (P = 0.024, Figure 1).


Spink2 modulates apoptotic susceptibility and is a candidate gene in the Rgcs1 QTL that affects retinal ganglion cell death after optic nerve damage.

Dietz JA, Maes ME, Huang S, Yandell BS, Schlamp CL, Montgomery AD, Allingham RR, Hauser MA, Nickells RW - PLoS ONE (2014)

DBA/2J.BALBRgcs1 substrain mice exhibit a susceptible phenotype after optic nerve crush.Bar graph showing cell loss after optic nerve crush (mean ± sem) in DBA/2J mice carrying the BALB/cByJ Rgcs1 allele (C). Mice with the CC allele exhibit a significantly greater percentage of cell loss in the ganglion cell layer than either DD or DC mice (P = 0.024, CC compared to the DD and DC animals combined). This difference in phenotype mimics the difference between purebred DBA/2J mice compared to purebred BALB/cByJ mice [10]. A minimum of 20 mice was assayed per group.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3974755&req=5

pone-0093564-g001: DBA/2J.BALBRgcs1 substrain mice exhibit a susceptible phenotype after optic nerve crush.Bar graph showing cell loss after optic nerve crush (mean ± sem) in DBA/2J mice carrying the BALB/cByJ Rgcs1 allele (C). Mice with the CC allele exhibit a significantly greater percentage of cell loss in the ganglion cell layer than either DD or DC mice (P = 0.024, CC compared to the DD and DC animals combined). This difference in phenotype mimics the difference between purebred DBA/2J mice compared to purebred BALB/cByJ mice [10]. A minimum of 20 mice was assayed per group.
Mentions: The Rgcs1 QTL from BALB/cByJ mice was identified as a recessive allele that was linked to greater cell loss after optic nerve crush in these mice. To test further the ability of this region to modulate the cell death phenotype in the resistant DBA/2J strain, the region of chromosome 5 flanked by microsatellite markers D5Mit254 (34 cM) and D5Mit338 (59 cM) was bred onto the DBA/2J background through 10 successive generations. Substrain mice, heterozygous and homozygous for the BALB/cByJ locus were then subjected to the optic nerve crush procedure at 8 weeks of age and compared to pure bred DBA/2J animals. DBA/2J mice exhibit retinal ganglion cell loss after optic nerve damage [1], but the rate and amount of cell loss is less than other strains [10], which is why they were classified as the “resistant” strain. Consistent with previous studies, mice homozygous for the BALB/cByJ Rgcs1 region exhibited significantly more cell loss (to levels similar to pure bred BALB/cByJ mice – data not shown) compared to mice carrying the DBA/2J allele (P = 0.024, Figure 1).

Bottom Line: In this region, a single gene (Spink2) is the most likely candidate for this effect.This gene is also polymorphic between resistant and susceptible strains, containing a single conserved amino acid change (threonine to serine) and a 220 bp deletion in intron 1 that may quantitatively alter endogenous expression levels between strains.Overexpression of the different variants of Spink2 in D407 tissue culture cells also increases their susceptibility to the apoptosis-inducing agent staurosporine in a manner consistent with the differential susceptibility between the DBA/2J and BALB/cByJ strains.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States of America.

ABSTRACT
The Rgcs1 quantitative trait locus, on mouse chromosome 5, influences susceptibility of retinal ganglion cells to acute damage of the optic nerve. Normally resistant mice (DBA/2J) congenic for the susceptible allele from BALB/cByJ mice exhibit susceptibility to ganglion cells, not only in acute optic nerve crush, but also to chronic inherited glaucoma that is characteristic of the DBA/2J strain as they age. SNP mapping of this QTL has narrowed the region of interest to 1 Mb. In this region, a single gene (Spink2) is the most likely candidate for this effect. Spink2 is expressed in retinal ganglion cells and is increased after optic nerve damage. This gene is also polymorphic between resistant and susceptible strains, containing a single conserved amino acid change (threonine to serine) and a 220 bp deletion in intron 1 that may quantitatively alter endogenous expression levels between strains. Overexpression of the different variants of Spink2 in D407 tissue culture cells also increases their susceptibility to the apoptosis-inducing agent staurosporine in a manner consistent with the differential susceptibility between the DBA/2J and BALB/cByJ strains.

Show MeSH
Related in: MedlinePlus