We use zebrafish to identify genes that may be important for human lens and anterior segment disease. Lens optical clarity is achieved and maintained throughout life by the regulation and integration of lens cell proliferation and differentiation. Disrupting the genetic control of these processes can lead to cataracts, or lens opacity, which are the leading cause of blindness worldwide. Zebrafish lens development, structural organization and gene functions are largely conserved with humans. Therefore, zebrafish is an excellent model to study the molecular mechanisms controlling lens formation and the maintenance of lens clarity.
Different strategies are utilized to identify and characterize genes that function in lens formation. Chemical mutagenesis identified several zebrafish eye mutants characterized by defects in lens development or growth. Mutation mapping and positional cloning approaches identify the genes responsible for the mutant phenotypes. Gene and protein expression changes in the mutants compared to wild type help determine the molecular basis for the lens defects. In addition, zebrafish orthologs of mammalian lens development genes are cloned and analyzed to determine their functions for zebrafish lens development. Anti-sense-mediated gene knockdown by morpholino injections and transgenic over-expression provide data to determine the roles these genes play in the lens. These studies may also identify factors critical for eye development because the lens and other eye tissues display some degree of developmental interdependence.
Zebrafish model for human lens disease. A and B: Zebrafish lens cell types and organization are nearly identical to human. Lens epithelial cells (arrowheads) continue to proliferate and differentiate into secondary fiber cells (arrows) throughout life. C: Zebrafish lens fiber cells viewed by scanning electron microscopy display interdigitating processes (arrows) along their lateral faces, similar to mammalian lens fibers.