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S. Chen, N. M. A. Tran; Mechanistically Distinct Mouse Models for CRX-Associated Dominant Retinopathies. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3486.
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The cone-rod homeobox (CRX) transcription factor is necessary for development and maintenance of photoreceptor function by coordinately regulating the expression of many photoreceptor genes. CRX mutations are linked to the dominant retinopathies Leber’s congenital amaurosis (LCA), cone-rod dystrophy (CRD) and retinitis pigmentosa (RP). However, the Crx knockout mouse does not show a dominant phenotype and thus fails to model these human diseases. To understand the active roles of mutant CRX proteins in disease pathogenesis, we have created two knock-in (K-IN) mice, R90W and E168d2, which carry mutations associated with distinct forms of human disease. This study was designed to evaluate these mice as animal models for CRX-associated diseases.
The retinas of R90W and E168d2 K-IN mice were characterized for structural integrity using histopathological measures, retinal function using electroretinography, and CRX target gene expression using qRT-PCR and immunohistochemistry at developmental and adult stages.
The R90W and E168d2 lines show distinct retinal phenotypes. Heterozygous R90W (R90W/+) mice exhibit a developmental delay in opsin expression, but recover and form a fully functional mature retina. In contrast, heterozygous E168d2/+ mice show impaired cone/rod gene expression, outer nuclear layer morphology and retinal function that persist throughout life, resembling LCA or early onset CRD. No apparent retinal degeneration was observed in R90W/+ or E168d2/+ through one-year of age. Homozygous R90W and E168d2 mice lack photoreceptor outer segments, produce null ERG responses, and show severely impaired rod/cone gene expression. Their photoreceptors degenerate more rapidly than those of Crx-/- mice. E168d2 homozygotes develop the most severe defects among all Crx mutant lines studied.
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