Requirement for Zebrafish Ataxin-7 in Differentiation of Photoreceptors and Cerebellar Neurons

Constantin Yanicostas, Elisa Barbieri, Masahiko Hibi, Alexis Brice, Giovanni Stevanin, Nadia Soussi-Yanicostas
PLoS ONE. 2012-11-30; 7(11): e50705
DOI: 10.1371/JOURNAL.PONE.0050705

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1. PLoS One. 2012;7(11):e50705. doi: 10.1371/journal.pone.0050705. Epub 2012 Nov 30.

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

Yanicostas C(1), Barbieri E, Hibi M, Brice A, Stevanin G, Soussi-Yanicostas N.

Author information:
(1)INSERM, U676, Hôpital Robert Debré, Paris, France.

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.

DOI: 10.1371/journal.pone.0050705
PMCID: PMC3511343
PMID: 23226359 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus