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

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

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-7
  • Cell Differentiation* / drug effects
  • Cerebellum / cytology*
  • Cerebellum / drug effects
  • Cerebellum / embryology
  • Embryonic Development / drug effects
  • Humans
  • Muscles / embryology
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology*
  • Neurons / drug effects
  • Peptide Fragments / pharmacology
  • Photoreceptor Cells, Vertebrate / cytology*
  • Photoreceptor Cells, Vertebrate / drug effects
  • Photoreceptor Cells, Vertebrate / metabolism
  • Spinal Cord / embryology
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish / metabolism*
  • Zebrafish Proteins / chemistry
  • Zebrafish Proteins / deficiency
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*

Substances

  • ATXN7 protein, human
  • Ataxin-7
  • Nerve Tissue Proteins
  • Peptide Fragments
  • Zebrafish Proteins

Grant support

This work was supported by the Institut National de la Santé et de la Recherche Médicale (Inserm), Avenir programs (Nos. R04190SP and R05245DS), the Association Française contre les Myopathies (AFM) and the Agence Nationale de la Recherche (ANR, Grant “SCA7”). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.