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Maria Iribarne, Yuko Nishiwaki, Eri Oguri, Masato Araragi, Shohei Nakamura, Ichiro Masai; AIPL1 mutation causes cone photoreceptor degeneration in zebrafish through dysfunction of PDE6c. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5427.
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© ARVO (1962-2015); The Authors (2016-present)
In human and mouse, Aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) is expressed in photoreceptors and required for stability and membrane anchoring of a phototransduction molecule, cGMP-phosphodiesterase 6 (PDE6). Genetic mutations of AIPL1 are linked to Leber congenital amaurosis 4 (LCA4) in human. Since genetic mutations of PDE6 also cause photoreceptor degeneration, chronically elevated levels of cGMP is toxic to photoreceptors. Purpose of this study is to understand molecular mechanism underlying photoreceptor cell death in response to dysfunctions of AIPL1/PDE6.
Zebrafish wild-type, AIPL1 and PDE6c mutant strains were used. Expression of AIPL1 mRNA was examined in 1 year-old adult zebrafish retina by in situ hybridization. To identify AIPL1 mutant embryos, visual response was measured at 5-7 dpf. Seven dpf wild-type and AIPL1 mutant embryos were used for immunohisto-labeling and western blot analysis with anti-PDE6c antibody. cGMP concentration was measured using 6-7 dpf wild-type and AIPL1 mutant embryos. Photoreceptor survival in AIPL1 mutant was examined by labeling of 7 dpf retinal sections with a zebrafish cone photoreceptor marker zpr1.
We examined the role of AIPL1 in photoreceptor functions using zebrafish as human disease model. Two AIPL1 genes were annotated on zebrafish genome, namely AIPL1a and AIPL1b. In adult retina, AIPL1a was expressed in rods and UV cones, whereas AIPL1b was expressed in all types of cones. We previously reported that photopic vision and cone photoreceptor survival are affected in zebrafish cone-specific PDE6 subunit PDE6c mutant. APIL1b mutant showed no photopic visual response and a very similar cone-specific degeneration to PDE6c mutant. Furthermore, PDE6c expression was decreased and, if exist, abnormally localized in AIPL1b mutant photoreceptors. cGMP level was elevated in AIPL1b mutant. Finally, AIPL1b mutation genetically enhanced photoreceptor degeneration in PDE6c mutant.
Our findings indicate that AIPL1b is required for phototransduction and survival of cones in zebrafish. Biochemically, AIPL1b regulates PDE6c functions, suggesting a phenotypic similarity between human LCA4 and zebrafish AIPL1 mutant. Thus, zebrafish AIPL1b mutant provides a good model for understanding mechanism underlying photoreceptor degeneration in human LCA4.
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