A conserved role of αA-crystallin in the development of the zebrafish embryonic lens

alpha A- and alpha B-crystallins are small heat shock proteins that bind thermodynamically destabilized proteins thereby inhibiting their aggregation. Highly expressed in the mammalian lens, the alpha-crystallins have been postulated to play a critical role in the maintenance of lens optical properties by sequestering age-damaged proteins prone to aggregation as well as through a multitude of roles in lens epithelial cells. Here, we have examined the role of alpha-crystallins in the development of the vertebrate zebrafish lens. For this purpose, we have carried out morpholino-mediated knockdown of alpha A-, alpha Ba- and alpha Bb-crystallin and characterized the gross morphology of the lens. We observed lens abnormalities, including increased reflectance intensity, as a consequence of the interference with expression of these proteins. These abnormalities were less frequent in transgenic zebrafish embryos expressing rat alpha A-crystallin suggesting a specific role of alpha-crystallins in embryonic lens development. To extend and confirm these findings, we generated an alpha A-crystallin knockout zebrafish line. A more consistent and severe lens phenotype was evident in maternal/zygotic alpha A-crystallin mutants compared to those observed by morpholino knockdown. The penetrance of the lens phenotype was reduced by transgenic expression of rat alpha A-crystallin and its severity was attenuated by maternal alpha A-crystallin expression. These findings demonstrate that the role of alpha-crystallins in lens development is conserved from mammals to zebrafish and set the stage for using the embryonic lens as a model system to test mechanistic aspects of alpha-crystallin chaperone activity and to develop strategies to fine-tune protein protein interactions in aging and cataracts. (C) 2015 Elsevier Ltd. All rights reserved.