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Eye disorders and Zebrafish
Retinitis pigmentosa eye disease

The film "Zebrafish and the human eye disorders" in this package shows how zebrafish have been employed to learn more about the functions and components of the human eye. The corresponding genes, so the genetics, can only be studied in an appropriate model system, such as the zebrafish.

It is impossible to study or know everything about every organism. Therefore it is wise to agree that specific studies are done in specific organisms which are convenient to grow and keep, ethical to use, fit to the task and that will provide rapid answers. In biology therefore different model systems are used to solve different research questions. The zebrafish has been employed, amongst other areas of research, to study the development and components of the visual system. It is expected that analyses can be done, for instance with mutants, that are impossible to be carried out in humans. Much of the zebrafish genome has been sequenced, allowing researchers to identify human versions of zebrafish genes and vice versa.

Zebrafish in general are amendable to large-scale genetic screens because they can be maintained and bred easily. The species is very fertile with an average of 100 offspring per week per pair, and embryos are transparent, allowing unobstructed access to the researcher. Fertilization and subsequent embryonic development take place outside of the mother. As an evolutionary consequence, functional sensory systems develop rapidly, so that predators can be avoided and feeding can commence.

Embryos are free swimming and actively pursuing food particles once their swim bladders are inflated at 5 days postfertilization. In the optomotor (eye -> muscle) response, the larva swims to follow moving visual stimuli about 6 days after fertilization. This provides the opportunity to use their visually mediated behavior to screen chemically mutagenized strains for defects in vision. One of the first tests that can be done is to analyse changes in the distribution of melanin pigment in the skin of the zebrafish larvae in response to ambient light levels. The skin contains star-shaped melanophores that are filled with melanosomes (melanin granules). A light response is mediated by a direct projection of the retina to the hypothalamus, which in turn, activates the secretion of two hormones from the pituitary, which acts on the melanophores. Mutants which do not show this response can be analysed to see whether the defect is located in the developing eye.

In the adult zebrafish a number of visually mediated escape responses have also proven to be useful for screening mutations of the visual system. The fish visual system, lacking higher cortical processing areas in the brain, is still capable of performing a number of visual tasks, which were long thought to be exclusive to animals with a visual cortex, thus even extending the possibilities of the model.

Most of the mutants that researchers found to be behaviorally blind turned out to be defective in the survival of photoreceptors in the outer retina. In human diseases outer retinal dystrophies are also the most common cause for congenital blindness. These zebrafish mutants may be valuable examples to understand heritable human retinal dystrophies and may contribute to the understanding of age-related macula dystrophies as well. More advanced visual assays will identify mutations affecting more subtle defects of the visual system, for instance, defects in fine-tuning of visual sensitivity and processing. A scientific description of the experimental methods and the range of zebrafish mutants with defects in the visual system can be found in reviews by Stephan C.F. Neuhauss (2003Neuhauss.pdf) and Valerie C. Fleisch and Stephan C.F. Neuhauss (Fleisch ZF Review 06.pdf).

In 2004 the European Commission awarded 12 million Euros for five years of zebrafish research to a consortium of 15 European institutions, led by the Max Planck Institute for Developmental Biology. The ZF-MODELS consortium establishes zebrafish models for human diseases and discovers genes that will lead to the identification of new drug targets and gain fundamental insights into human development. The website of this research project is at http://www.zf-models.org/.