Genetic context determines susceptibility to intraocular pressure elevation in a mouse pigmentary glaucoma

University of Iowa, Iowa City, Iowa, United States
BMC Biology (Impact Factor: 7.98). 02/2006; 4(1):20. DOI: 10.1186/1741-7007-4-20
Source: PubMed


DBA/2J (D2) mice develop an age-related form of glaucoma. Their eyes progressively develop iris pigment dispersion and iris atrophy followed by increased intraocular pressure (IOP) and glaucomatous optic nerve damage. Mutant alleles of the Gpnmb and Tyrp1 genes are necessary for the iris disease, but it is unknown whether alleles of other D2 gene(s) are necessary for the distinct later stages of disease. We initiated a study of congenic strains to further define the genetic requirements and disease mechanisms of the D2 glaucoma.
To further understand D2 glaucoma, we created congenic strains of mice on the C57BL/6J (B6) genetic background. B6 double-congenic mice carrying D2-derived Gpnmb and Tyrp1 mutations develop a D2-like iris disease. B6 single-congenics with only the Gpnmb and Tyrp1 mutations develop milder forms of iris disease. Genetic epistasis experiments introducing a B6 tyrosinase mutation into the congenic strains demonstrated that both the single and double-congenic iris diseases are rescued by interruption of melanin synthesis. Importantly, our experiments analyzing mice at ages up to 27 months indicate that the B6 double-congenic mice are much less prone to IOP elevation and glaucoma than are D2 mice.
As demonstrated here, the Gpnmb and Tyrp1 iris phenotypes are both individually dependent on tyrosinase function. These results support involvement of abnormal melanosomal events in the diseases caused by each gene. In the context of the inbred D2 mouse strain, the glaucoma phenotype is clearly influenced by more genes than just Gpnmb and Tyrp1. Despite the outward similarity of pigment-dispersing iris disease between D2 and the B6 double-congenic mice, the congenic mice are much less susceptible to developing high IOP and glaucoma. These new congenic strains provide a valuable new resource for further studying the genetic and mechanistic complexity of this form of glaucoma.

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Available from: Simon WM John, Apr 10, 2014
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    • "The tracking of early microglial changes in young DBA/2J mice offers the possibility optimizing the use of this chronic model, allowing the selection of young animals in which one or both eyes will likely progress to severe glaucoma at advanced ages, thus reducing the inter-individual variability in disease progression within experimental samples. This strategy should advance the already intense studies aimed at elucidating the complex mechanisms that underlie neurodegeneration in chronic glaucoma (Anderson et al., 2006; Jakobs, 2014; Nair et al., 2014; Rieck, 2013), and identify initiating events associated with disease onset or early progression potentially relevant to glaucoma patients. "
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    Full-text · Article · Mar 2015 · Disease Models and Mechanisms
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    • "In a previous study we introduced osteopontin (OPN) as a novel AH factor that increases with age in DBA/2J mice, a widely used animal model for glaucomatous neurodegeneration in the eye [14]–[19]. Moreover, OPN showed a significant correlation with the progressive degree of optic nerve degeneration and RGC loss in these mice [20]. "
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    ABSTRACT: The aqueous humor (AH) component transforming growth factor (TGF)-β2 is strongly correlated to primary open-angle glaucoma (POAG), and was shown to up-regulate glaucoma-associated extracellular matrix (ECM) components, members of the ECM degradation system and heat shock proteins (HSP) in primary ocular cells. Here we present osteopontin (OPN) as a new TGF-β2 responsive factor in cultured human optic nerve head (ONH) astrocytes. Activation was initially demonstrated by Oligo GEArray microarray and confirmed by semiquantitative (sq) RT-PCR, realtime RT-PCR and western blot. Expressions of most prevalent OPN receptors CD44 and integrin receptor subunits αV, α4, α 5, α6, α9, β1, β3 and β5 by ONH astrocytes were shown by sqRT-PCR and immunofluorescence labeling. TGF-β2 treatment did not affect their expression levels. OPN did not regulate gene expression of described TGF-β2 targets shown by sqRT-PCR. In MTS-assays, OPN had a time- and dose-dependent stimulating effect on the metabolic activity of ONH astrocytes, whereas TGF-β2 significantly reduced metabolism. OPN signaling via CD44 mediated a repressive outcome on metabolic activity, whereas signaling via integrin receptors resulted in a pro-metabolic effect. In summary, our findings characterize OPN as a TGF-β2 responsive factor that is not involved in TGF-β2 mediated ECM and HSP modulation, but affects the metabolic activity of astrocytes. A potential involvement in a protective response to TGF-β2 triggered damage is indicated, but requires further investigation.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "The etiology of IOP elevation and glaucoma in D2 mice is clearly complex, involving multiple factors. Although mutations in Gpnmb and Tyrp1 are sufficient to cause iris disease, our previous work indicates that additional D2 specific alleles at other loci are needed for progression to high IOP and glaucoma [31]. Here, we have ruled out CD94 deficiency as a factor necessary for iris disease or progression to high IOP and glaucoma in D2 mice. "
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    ABSTRACT: The molecular mechanisms causing pigment dispersion syndrome (PDS) and the pathway(s) by which it progresses to pigmentary glaucoma are not known. Mutations in two melanosomal protein genes (Tyrp1b and GpnmbR150X) are responsible for pigment dispersing iris disease, which progresses to intraocular pressure (IOP) elevation and subsequent glaucoma in DBA/2J mice. Melanosomal defects along with ocular immune abnormalities play a role in the propagation of pigment dispersion and progression to IOP elevation. Here, we tested the role of specific immune components in the progression of the iris disease and high IOP. We tested the role of NK cells in disease etiology by genetically modifying the B6.D2-GpnmbR150X Tyrp1b strain, which develops the same iris disease as DBA/2J mice. Our findings demonstrate that neither diminishing NK mediated cytotoxic activity (Prf1 mutation) nor NK cell depletion (Il2rg mutation) has any influence on the severity or timing of GpnmbR150X Tyrp1b mediated iris disease. Since DBA/2J mice are deficient in CD94, an important immune modulator that often acts as an immune suppressor, we generated DBA/2J mice sufficient in CD94. Sufficiency of CD94 failed to alter either the iris disease or the subsequent IOP elevation. Additionally CD94 status had no detected effect on glaucomatous optic nerve damage. Our previous data implicate immune components in the manifestation of pigment dispersion and/or IOP elevation in DBA/2J mice. The current study eliminates important immune components, specifically NK cells and CD94 deficiency, as critical in the progression of iris disease and glaucoma. This narrows the field of possible immune components responsible for disease progression.
    Full-text · Article · Mar 2014 · BMC Genetics
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