PUBLICATION

Noncell-autonomous photoreceptor degeneration in a zebrafish model of choroideremia

Authors
Krock, B.L., Bilotta, J., and Perkins, B.D.
ID
ZDB-PUB-070330-8
Date
2007
Source
Proceedings of the National Academy of Sciences of the United States of America   104(11): 4600-4605 (Journal)
Registered Authors
Bilotta, Joe, Perkins, Brian
Keywords
retinal degeneration, retinal pigment epithelium
MeSH Terms
  • Alleles
  • Animals
  • Choroideremia/genetics*
  • Choroideremia/pathology
  • Disease Models, Animal
  • Electroretinography
  • Microscopy, Electron, Transmission
  • Models, Biological
  • Mosaicism
  • Mutation*
  • Photoreceptor Cells, Vertebrate/pathology*
  • Pigment Epithelium of Eye/metabolism
  • Retinal Degeneration/genetics
  • Rod Opsins/metabolism
  • Time Factors
  • Zebrafish
PubMed
17360570 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
Choroideremia is an X-linked hereditary retinal degeneration resulting from mutations in the Rab escort protein-1 (REP1). The Rep1 protein facilitates posttranslational modification of Rab proteins, which regulate intracellular trafficking in the retinal pigment epithelium (RPE) and photoreceptors and are likely involved in the removal of outer segment disk membranes by the RPE. A critical question for potential treatment of choroideremia is whether photoreceptor degeneration results from autonomous defects in opsin transport within the photoreceptor or as a nonautonomous and secondary consequence of RPE degeneration. To address this question, we have characterized the retinal pathology in zebrafish rep1 mutants, which carry a recessive nonsense mutation in the REP1 gene. Zebrafish rep1 mutants exhibit degeneration of the RPE and photoreceptors and complete loss of visual function as measured by electroretinograms. In the mutant RPE, photoreceptor outer segment material was not effectively eliminated, and large vacuoles were observed. However, opsin trafficking in photoreceptors occurred normally. Mosaic analysis revealed that photoreceptor degeneration was nonautonomous and required contact with the mutant RPE as mutant photoreceptors were rescued in wild-type hosts and wild-type photoreceptors degenerated in mutant hosts. We conclude that mutations in REP1 disrupt cellular processes in the RPE, which causes photoreceptor death as a secondary consequence. These results suggest that therapies that correct the RPE may successfully rescue photoreceptor loss in choroideremia.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes