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First published online 25 May 2006
doi: 10.1242/dev.02424
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A-crystallin expression prevents 
-crystallin insolubility and cataract formation in the zebrafish cloche mutant lens
1 Vascular Biology Program/Department of Surgery, Children's Hospital and
Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
2 Department of Molecular and Developmental Biology, Institute of Medical
Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639,
Japan.
3 Howard Hughes Medical Institute and Division of Hematology/Oncology,
Children's Hospital, Harvard Medical School, Boston, MA 02115,USA.
4 Vascular Biology Program/Department of Pathology, Children's Hospital and
Harvard Medical School, Boston, MA 02115, USA.
Author for correspondence (e-mail:
michael.klagsbrun{at}childrens.harvard.edu)
Accepted 3 May 2006
Cataracts, the loss of lens transparency, are the leading cause of human
blindness. The zebrafish embryo, with its transparency and relatively large
eyes, is an excellent model for studying ocular disease in vivo. We found that
the zebrafish cloche mutant, both the clochem39
and clocheS5 alleles, which have defects in hematopoiesis
and blood vessel development, also have lens cataracts. Quantitative
examination of the living zebrafish lens by confocal microscopy showed
significant increases in lens reflectance. Histological analysis revealed
retention of lens fiber cell nuclei owing to impeded terminal differentiation.
Proteomics identified 
-crystallin as a protein that was substantially
diminished in cloche mutants. Crystallins are the major structural
proteins in mouse, human and zebrafish lens. Defects in crystallins have
previously been shown in mice and humans to contribute to cataracts. The loss
of -crystallin protein in cloche was not due to lowered mRNA
levels but rather to -crystallin protein insolubility.
A-crystallin is a chaperone that protects proteins from misfolding and
becoming insoluble. The cloche lens is deficient in both
A-crystallin mRNA and protein during development from 2-5 dpf.
Overexpression of exogenous A-crystallin rescued the
cloche lens phenotype, including solubilization of
-crystallin, increased lens transparency and induction of lens fiber
cell differentiation. Taken together, these results indicate that
A-crystallin expression is required for normal lens
development and demonstrate that cataract formation can be prevented in vivo.
In addition, these results show that proteomics is a valuable tool for
detecting protein alterations in zebrafish.
Key words: Cataract, Crystallin, Chaperone, Cloche, Eye, Lens, Zebrafish, cryaa
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