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Gemma Marfany, Vasileios Toulis, Maria do Carmo Costa; The deubiquitinating enzyme Ataxin-3 is relevant for retina formation and differentiation in mouse and zebrafish. Invest. Ophthalmol. Vis. Sci. 2017;58(8):599.
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© ARVO (1962-2015); The Authors (2016-present)
An expanded CAG repeat on the ATXN3 gene, encoding the deubiquitinating enzyme ATXN3, causes Spinocerebellar Ataxia Type 3 (SCA3), a late onset autosomal dominant neurodegenerative disorder. The physiological role of ATXN3, however, is not completely understood. Since deubiquitination seems to play a crucial role in photoreceptor development and differentiation, we aimed to explore the function of ATXN3 in retinal development combining mouse knockout and zebrafish knockdown animal models.
Functional analysis in zebrafish embryos was approached by knocking-down Atxn3 expression to analyze the morphant phenotypes and attempt genetic rescue by injection of the human orthologous mRNA. Deletion of Atxn3 in knockout mouse retinas was confirmed both at RNA and protein levels. Retinal phenotype of P60 and 2-year old Atxn3 knockout mice was studied by immunofluorescence detection, transmission electron microscopy and photoreceptor isolation for a more detailed description.
A comparative Atxn3 expression map in mouse and zebrafish retinas has been drawn, showing evolutionary conservation in mRNA localization. The zebrafish Atxn3 knockdown morphants showed severe ocular morphological alterations, with a defective formation of retinal structures. Evolutionary conservation was further supported by phenotypic rescue with human ATXN3 mRNAs. While cell loss was not observed in Atxn3 knockout mouse retinas, these showed a significant elongation of the photoreceptors (rods and cones), with a simultaneous mislocalization of cone specific phototransduction proteins.
These results support the involvement of ATXN3 in the formation and differentiation of the vertebrate retina, especially of photoreceptors, pointing this gene as a good candidate for causing inherited retinal dystrophies.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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