Requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.

The expansion of a polyglutamine (polyQ) tract in the N-terminal region of ataxin-7 (atxn7) is the causative event in spinocerebellar ataxia type 7 (SCA7), an autosomal dominant neurodegenerative disorder mainly characterized by progressive, selective loss of rod-cone photoreceptors and cerebellar P...

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Autores principales:	Constantin Yanicostas, Elisa Barbieri, Masahiko Hibi, Alexis Brice, Giovanni Stevanin, Nadia Soussi-Yanicostas
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/795876285dfc4cdcb24a324687e221ea
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spelling	oai:doaj.org-article:795876285dfc4cdcb24a324687e221ea2021-11-18T08:06:44ZRequirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.1932-620310.1371/journal.pone.0050705https://doaj.org/article/795876285dfc4cdcb24a324687e221ea2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23226359/?tool=EBIhttps://doaj.org/toc/1932-6203The expansion of a polyglutamine (polyQ) tract in the N-terminal region of ataxin-7 (atxn7) is the causative event in spinocerebellar ataxia type 7 (SCA7), an autosomal dominant neurodegenerative disorder mainly characterized by progressive, selective loss of rod-cone photoreceptors and cerebellar Purkinje and granule cells. The molecular and cellular processes underlying this restricted neuronal vulnerability, which contrasts with the broad expression pattern of atxn7, remains one of the most enigmatic features of SCA7, and more generally of all polyQ disorders. To gain insight into this specific neuronal vulnerability and achieve a better understanding of atxn7 function, we carried out a functional analysis of this protein in the teleost fish Danio rerio. We characterized the zebrafish atxn7 gene and its transcription pattern, and by making use of morpholino-oligonucleotide-mediated gene inactivation, we analysed the phenotypes induced following mild or severe zebrafish atxn7 depletion. Severe or nearly complete zebrafish atxn7 loss-of-function markedly impaired embryonic development, leading to both early embryonic lethality and severely deformed embryos. More importantly, in relation to SCA7, moderate depletion of the protein specifically, albeit partially, prevented the differentiation of both retina photoreceptors and cerebellar Purkinje and granule cells. In addition, [1-232] human atxn7 fragment rescued these phenotypes showing strong function conservation of this protein through evolution. The specific requirement for zebrafish atxn7 in the proper differentiation of cerebellar neurons provides, to our knowledge, the first in vivo evidence of a direct functional relationship between atxn7 and the differentiation of Purkinje and granule cells, the most crucial neurons affected in SCA7 and most other polyQ-mediated SCAs. These findings further suggest that altered protein function may play a role in the pathophysiology of the disease, an important step toward the development of future therapeutic strategies.Constantin YanicostasElisa BarbieriMasahiko HibiAlexis BriceGiovanni StevaninNadia Soussi-YanicostasPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e50705 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Constantin Yanicostas Elisa Barbieri Masahiko Hibi Alexis Brice Giovanni Stevanin Nadia Soussi-Yanicostas Requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.
description	The expansion of a polyglutamine (polyQ) tract in the N-terminal region of ataxin-7 (atxn7) is the causative event in spinocerebellar ataxia type 7 (SCA7), an autosomal dominant neurodegenerative disorder mainly characterized by progressive, selective loss of rod-cone photoreceptors and cerebellar Purkinje and granule cells. The molecular and cellular processes underlying this restricted neuronal vulnerability, which contrasts with the broad expression pattern of atxn7, remains one of the most enigmatic features of SCA7, and more generally of all polyQ disorders. To gain insight into this specific neuronal vulnerability and achieve a better understanding of atxn7 function, we carried out a functional analysis of this protein in the teleost fish Danio rerio. We characterized the zebrafish atxn7 gene and its transcription pattern, and by making use of morpholino-oligonucleotide-mediated gene inactivation, we analysed the phenotypes induced following mild or severe zebrafish atxn7 depletion. Severe or nearly complete zebrafish atxn7 loss-of-function markedly impaired embryonic development, leading to both early embryonic lethality and severely deformed embryos. More importantly, in relation to SCA7, moderate depletion of the protein specifically, albeit partially, prevented the differentiation of both retina photoreceptors and cerebellar Purkinje and granule cells. In addition, [1-232] human atxn7 fragment rescued these phenotypes showing strong function conservation of this protein through evolution. The specific requirement for zebrafish atxn7 in the proper differentiation of cerebellar neurons provides, to our knowledge, the first in vivo evidence of a direct functional relationship between atxn7 and the differentiation of Purkinje and granule cells, the most crucial neurons affected in SCA7 and most other polyQ-mediated SCAs. These findings further suggest that altered protein function may play a role in the pathophysiology of the disease, an important step toward the development of future therapeutic strategies.
format	article
author	Constantin Yanicostas Elisa Barbieri Masahiko Hibi Alexis Brice Giovanni Stevanin Nadia Soussi-Yanicostas
author_facet	Constantin Yanicostas Elisa Barbieri Masahiko Hibi Alexis Brice Giovanni Stevanin Nadia Soussi-Yanicostas
author_sort	Constantin Yanicostas
title	Requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.
title_short	Requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.
title_full	Requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.
title_fullStr	Requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.
title_full_unstemmed	Requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.
title_sort	requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/795876285dfc4cdcb24a324687e221ea
work_keys_str_mv	AT constantinyanicostas requirementforzebrafishataxin7indifferentiationofphotoreceptorsandcerebellarneurons AT elisabarbieri requirementforzebrafishataxin7indifferentiationofphotoreceptorsandcerebellarneurons AT masahikohibi requirementforzebrafishataxin7indifferentiationofphotoreceptorsandcerebellarneurons AT alexisbrice requirementforzebrafishataxin7indifferentiationofphotoreceptorsandcerebellarneurons AT giovannistevanin requirementforzebrafishataxin7indifferentiationofphotoreceptorsandcerebellarneurons AT nadiasoussiyanicostas requirementforzebrafishataxin7indifferentiationofphotoreceptorsandcerebellarneurons
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Requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.

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