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Yvon Trottier, Samantha Carrillo-Rosas, Alice Karam, Nadia Messaddeq, Chantal Weber; Role of ATXN7 in the Development of Vertebrate Retina; Implication for the Cone-Rod Dystrophy of SCA7 Patients. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1776.
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© ARVO (1962-2015); The Authors (2016-present)
The cone-rod dystrophy affecting Spinocerebellar ataxia 7 (SCA7) patients is caused by a polyglutamine expansion in ATXN7. The retina of SCA7 mice shows limited cell death, but massive loss of photoreceptor outer segments, which correlates with mislocalization of ATXN7. This suggests that partial loss of function of ATXN7 could account for this atypical retina phenotype. Yet the physiological role of ATXN7 in the eye is unknown. We hypothesize that ATXN7 has authetic functions in the development and maintenance of the retina.
Morpholino antisense oligonucleotides (MO) were used to inactivate the ATXN7 ortholog (atxn7) in the zebrafish AB line and SoFa line, which expresses different fluorescent proteins in each retinal neuron layers. Eye phenotypes of fish injected with MOatxn7 or MOctrl were analyzed from 24 to 120 hours post-fertilization (hpf) at morphological, histological and ultrastructural levels using confocal and electron microscopy. In situ hybridization (ISH) was used to assess the expression of genes involved in eye development.
Atxn7 morphants showed severe eye anomalies at 24 hpf including coloboma and extrusion of pigmented epithelium (PE) into the brain (50% of affected eyes by 120 hpf). Longitudinal follow up of atxn7 inactivation in the SoFa line revealed a strong delay in the initiation of retinal neuron differentiation and anomalies in the timing and spatial localization of differentiating neurons. Electron micrographs of less severely affected morphant eyes showed normal layering of retinal neurons, but complete absence of photoreceptor outer segments and vacuolization in the PE. ISH on atxn7 morphants indicated a reduced expression of crx -an essential transcription factor controlling retinal neuron differentiation. Shh expression was normal in atxn7 morphants, while vax1 and vax2, two genes regulated by the shh pathway and involved in optic stalk formation and eye closure showed reduced expression.
Zebrafish atxn7 plays an early role in the development of optic stalk and eye closure by regulating downstream of shh the expression of vax1 and vax2, and a later role in the differentiation of retinal neurons by controlling crx expression. Consistently, Crx is down-regulated in SCA7 mouse retina, supporting a partial loss of ATXN7 function in the pathology.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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