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Martin-Paul Agbaga, Blake Hopiavuori, Feng Li, Joel McRae, Richard Brush, Md Nawajes Mandal, Lea Marchette, Michael Elliott, Radha Ayyagari, Robert Anderson, ; Conditional Depletion of Retinal VLC-PUFAs Causes Retinal Dysfunction. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6106.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in the Elongation of Very Long chain fatty acids-4 (ELOVL4) gene cause autosomal dominant Stargardt macular dystrophy (STGD3). Others and ongoing studies in our lab suggest the retinal pathology might be caused by either expression of mutant-ELOVL4 or by depletion of retinal very long chain polyunsaturated fatty acids (VLC-PUFA). We hypothesized that if mutant-ELOVL4 contributes to retinal pathology in STGD3, then conditional expression of the mutant in the absence of wild-type ELOVL4, which leads to loss/depletion of retinal VLC-PUFA, would exacerbate retinal degeneration in conditional Elovl4 knock-in mice (cKI) that express only mutant ELOVL4 in the retina.
We mated mice expressing Cre recombinase in the neural retina under control of the CHX10 promoter (CHX10-Cre+) with Elovl4flox/flox mice to generate Cre+/Elovl4flox/flox. We then crossed the Cre+/Elovl4flox/flox mice with Elovl4wt/stgd3 mice to generate four genotypes: Cre-/Elovl4flox/wt, Cre+/Elovl4flox/wt, Cre-/Elovl4flox/stgd3, and Cre+/Elovl4flox/stgd3. We quantified VLC-PUFA levels by gas chromatography-mass spectrometry. Retinal function was determined at 1 year of age by scotopic and photopic electroretinography (ERG) to measure rod and cone function, respectively.
At 1 year of age, the Cre-/Elovl4flox/wt mice expressing two copies of WT ELOVL4, had significantly higher a- and b-wave maximal amplitude responses compared to the other three groups. There was no functional difference between mice expressing one WT ELOVL4 (Cre+/Elovl4flox/wt) or mice expressing one WT and one mutant copy (Cre-/Elovl4flox/stgd3). The Cre+/Elovl4flox/stgd3 mice expressing only mutant-ELOVL4 were functionally different only from mice expressing two copies of WT ELOVL4 (Cre-/Elovl4flox/wt). There were no differences in cone photoreceptor responses across the four groups.
Reduction in retinal VLC-PUFA leads to reduction in rod, but not cone, function. The expression of the mutant ELOVL4 did not exacerbate the loss of rod function. On the basis of this study, it appears that the loss of retinal function in STGD3 is due predominantly to reduction in retinal VLC-PUFA than to the expression of the mutant-ELOVL4protein.
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