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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 have more severe glaucomatous damage.(A) Intraocular pressures (IOP) of eyes from 3 month and 10 month DBA/2J wild type and substrain mice. Mice homozygous for the BALB/cByJ allele of Rgcs1 (CC) exhibit no difference in IOPs at either age (P = 0.275, 3 months; P = 0.889, 10 months) compared to mice carrying at least one DBA/2J allele for Rgcs1 (DD and DC, respectively). For CC mice data was collected from 15 and 42 eyes at 3 months and 10 months, respectively. For DC mice, data was collected from 28 and 41 eyes, respectively. For DD mice, data was collected from 20 and 136 eyes, respectively. (B) Bar graph showing the frequency of mild, moderate, and severe optic nerve damage in 10 month old DBA/2J mice carrying either the D or C alleles for Rgcs1. Mice homozygous for the BALB/c allele (CC) have a higher frequency of severe optic nerve damage than mice with the D allele (β2 P = 0.013, CC compared to the combined DD and DC animals). Nerves from 163, 90, and 40 DD, DC, and CC mice, respectively were scored. (C) Images of whole mounted retinas, surface stained with DAPI showing exemplars of mild, moderate, and severe damage. (D) Bar graph showing the mean retinal cell density of 10 month old DBA/2J mice. (*P<0.001, CC compared to DD and DC samples combined).
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pone-0093564-g002: DBA/2J.BALBRgcs1 substrain mice have more severe glaucomatous damage.(A) Intraocular pressures (IOP) of eyes from 3 month and 10 month DBA/2J wild type and substrain mice. Mice homozygous for the BALB/cByJ allele of Rgcs1 (CC) exhibit no difference in IOPs at either age (P = 0.275, 3 months; P = 0.889, 10 months) compared to mice carrying at least one DBA/2J allele for Rgcs1 (DD and DC, respectively). For CC mice data was collected from 15 and 42 eyes at 3 months and 10 months, respectively. For DC mice, data was collected from 28 and 41 eyes, respectively. For DD mice, data was collected from 20 and 136 eyes, respectively. (B) Bar graph showing the frequency of mild, moderate, and severe optic nerve damage in 10 month old DBA/2J mice carrying either the D or C alleles for Rgcs1. Mice homozygous for the BALB/c allele (CC) have a higher frequency of severe optic nerve damage than mice with the D allele (β2 P = 0.013, CC compared to the combined DD and DC animals). Nerves from 163, 90, and 40 DD, DC, and CC mice, respectively were scored. (C) Images of whole mounted retinas, surface stained with DAPI showing exemplars of mild, moderate, and severe damage. (D) Bar graph showing the mean retinal cell density of 10 month old DBA/2J mice. (*P<0.001, CC compared to DD and DC samples combined).

Mentions: DBA/2J mice also develop anterior chamber abnormalities leading to pathology of the trabecular meshwork and ocular hypertension [13], [16]. By 8 months of age, a majority of these animals exhibit elevated IOP and, by 10 months, glaucomatous pathology of the retina and optic nerve [14], [15]. DBA/2J mice congenic for the BALB/cByJ Rgcs1 allele (DBA/2J.BALBRgcs1) developed increased IOP with age, equivalent to IOP changes in DBA/2J animals (P = 0.889, Figure 2A). These mice, however, had more severe glaucomatous damage to both the optic nerve and retina, compared with pure bred and heterozygous age-matched mice (P = 0.013 for optic nerves and P<0.001 for retinas, Figure 2). These results support the hypothesis that the Rgcs1 locus can modify the level of glaucomatous damage in a manner consistent with the acute optic nerve damage paradigm.


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 have more severe glaucomatous damage.(A) Intraocular pressures (IOP) of eyes from 3 month and 10 month DBA/2J wild type and substrain mice. Mice homozygous for the BALB/cByJ allele of Rgcs1 (CC) exhibit no difference in IOPs at either age (P = 0.275, 3 months; P = 0.889, 10 months) compared to mice carrying at least one DBA/2J allele for Rgcs1 (DD and DC, respectively). For CC mice data was collected from 15 and 42 eyes at 3 months and 10 months, respectively. For DC mice, data was collected from 28 and 41 eyes, respectively. For DD mice, data was collected from 20 and 136 eyes, respectively. (B) Bar graph showing the frequency of mild, moderate, and severe optic nerve damage in 10 month old DBA/2J mice carrying either the D or C alleles for Rgcs1. Mice homozygous for the BALB/c allele (CC) have a higher frequency of severe optic nerve damage than mice with the D allele (β2 P = 0.013, CC compared to the combined DD and DC animals). Nerves from 163, 90, and 40 DD, DC, and CC mice, respectively were scored. (C) Images of whole mounted retinas, surface stained with DAPI showing exemplars of mild, moderate, and severe damage. (D) Bar graph showing the mean retinal cell density of 10 month old DBA/2J mice. (*P<0.001, CC compared to DD and DC samples combined).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3974755&req=5

pone-0093564-g002: DBA/2J.BALBRgcs1 substrain mice have more severe glaucomatous damage.(A) Intraocular pressures (IOP) of eyes from 3 month and 10 month DBA/2J wild type and substrain mice. Mice homozygous for the BALB/cByJ allele of Rgcs1 (CC) exhibit no difference in IOPs at either age (P = 0.275, 3 months; P = 0.889, 10 months) compared to mice carrying at least one DBA/2J allele for Rgcs1 (DD and DC, respectively). For CC mice data was collected from 15 and 42 eyes at 3 months and 10 months, respectively. For DC mice, data was collected from 28 and 41 eyes, respectively. For DD mice, data was collected from 20 and 136 eyes, respectively. (B) Bar graph showing the frequency of mild, moderate, and severe optic nerve damage in 10 month old DBA/2J mice carrying either the D or C alleles for Rgcs1. Mice homozygous for the BALB/c allele (CC) have a higher frequency of severe optic nerve damage than mice with the D allele (β2 P = 0.013, CC compared to the combined DD and DC animals). Nerves from 163, 90, and 40 DD, DC, and CC mice, respectively were scored. (C) Images of whole mounted retinas, surface stained with DAPI showing exemplars of mild, moderate, and severe damage. (D) Bar graph showing the mean retinal cell density of 10 month old DBA/2J mice. (*P<0.001, CC compared to DD and DC samples combined).
Mentions: DBA/2J mice also develop anterior chamber abnormalities leading to pathology of the trabecular meshwork and ocular hypertension [13], [16]. By 8 months of age, a majority of these animals exhibit elevated IOP and, by 10 months, glaucomatous pathology of the retina and optic nerve [14], [15]. DBA/2J mice congenic for the BALB/cByJ Rgcs1 allele (DBA/2J.BALBRgcs1) developed increased IOP with age, equivalent to IOP changes in DBA/2J animals (P = 0.889, Figure 2A). These mice, however, had more severe glaucomatous damage to both the optic nerve and retina, compared with pure bred and heterozygous age-matched mice (P = 0.013 for optic nerves and P<0.001 for retinas, Figure 2). These results support the hypothesis that the Rgcs1 locus can modify the level of glaucomatous damage in a manner consistent with the acute optic nerve damage paradigm.

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