PUBLICATION

Loss of zebrafish Ataxin-7, a SAGA subunit responsible for SCA7 retinopathy, causes ocular coloboma and malformation of photoreceptors

Authors
Carrillo-Rosas, S., Weber, C., Fievet, L., Messaddeq, N., Karam, A., Trottier, Y.
ID
ZDB-PUB-181118-11
Date
2018
Source
Human molecular genetics   28(6): 912-927 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Phenotype
  • Gene Editing
  • Genetic Predisposition to Disease*
  • Cell Differentiation
  • Coloboma/etiology*
  • Coloboma/metabolism*
  • Coloboma/pathology
  • Histones/metabolism
  • Animals
  • Animals, Genetically Modified
  • Body Patterning/genetics
  • Disease Models, Animal
  • Biomarkers
  • Immunohistochemistry
  • Organogenesis/genetics
  • Models, Biological
  • Protein Processing, Post-Translational
  • Zebrafish
  • Protein Subunits/deficiency*
  • Ataxin-7/deficiency*
  • Optic Nerve/embryology
  • Optic Nerve/metabolism
  • Photoreceptor Cells/metabolism*
  • Photoreceptor Cells/pathology
  • Gene Expression Regulation
  • Trans-Activators/chemistry
  • Trans-Activators/genetics*
  • Trans-Activators/metabolism
(all 28)
PubMed
30445451 Full text @ Hum. Mol. Genet.
Abstract
Polyglutamine expansion in Ataxin-7 results in Spinocerebellar ataxia type 7 (SCA7) and causes visual impairment. SCA7 photoreceptors progressively lose their outer segments, a structure essential for their visual function. Ataxin-7 is a subunit of the transcriptional coactivator Spt-Ada-Gcn5 Acetyltransferase (SAGA) complex, implicated in the development of the visual system in flies. To determine the function of Ataxin-7 in the vertebrate eye, we have inactivated Ataxin-7 in zebrafish. While Ataxin-7 depletion in flies led to gross retinal degeneration, in zebrafish it primarily results in ocular coloboma, a structural malformation responsible for pediatric visual impairment in human. Ataxin-7 inactivation leads to elevated Hedgehog signaling in the forebrain, causing an alteration of proximo-distal patterning of the optic vesicle during early eye development and coloboma. At later developmental stages, malformations of photoreceptors due to incomplete formation of their outer segments are observed, and correlate with altered expression of crx, a key transcription factor involved in the formation of photoreceptor outer segment. Therefore, we propose that a primary toxic effect of polyglutamine expansion is the alteration of Ataxin-7 function in the daily renewal of outer segment in SCA7. Together, our data indicate that Ataxin-7 plays an essential role in vertebrate eye morphogenesis and photoreceptor differentiation, and its loss of function may contribute to the development of human coloboma.
Genes / Markers
Figures
No images available
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cu2TgTransgenic Insertion
    jh1TgTransgenic Insertion
      q20TgTransgenic Insertion
        1 - 3 of 3
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        Human Disease / Model
        Human Disease Fish Conditions Evidence
        colobomaAB + MO1-atxn7standard conditionsTAS
        cone-rod dystrophyAB + MO1-atxn7standard conditionsTAS
        nerve fibre bundle defectAB + MO1-atxn7standard conditionsIC
        1 - 3 of 3
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        Sequence Targeting Reagents
        Fish
        Fish
        AB
        AB + CRISPR1-atxn7
        AB + MO1-atxn7
        AB + MO3-atxn7
        cu2Tg; jh1Tg; q20Tg
        cu2Tg; jh1Tg; q20Tg + MO1-atxn7
        1 - 6 of 6
        Show
        Antibodies
        Orthology
        Engineered Foreign Genes
        Marker Marker Type Name
        CFPEFGCFP
        EGFPEFGEGFP
        RFPEFGRFP
        1 - 3 of 3
        Show
        Mapping
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        Citation
        Carrillo-Rosas, S., Weber, C., Fievet, L., Messaddeq, N., Karam, A., Trottier, Y. (2018) Loss of zebrafish Ataxin-7, a SAGA subunit responsible for SCA7 retinopathy, causes ocular coloboma and malformation of photoreceptors. Human molecular genetics. 28(6):912-927.