The development and growth of the vertebrate eye must be perfectly coordinated in order to transmit correct visual images to the brain. The lens is responsible in part for coordinating eye growth but the underlying molecular and cellular mechanisms are unknown. We will investigate this problem in Astyanax mexicanus, a teleost species consisting of an eyed surface dwelling form (surface fish) and a blind cave-dwelling form (cavefish). Eye primordia are initially formed during cavefish development but subsequently arrest and degenerate, resulting in a blind adult. The first tissue to degenerate is the lens. Remarkably, transplanting a surface fish embryonic lens into a cavefish optic cup can restore a complete eye in adult cavefish. We propose to study the molecular and cellular basis of lens regulation of eye growth and development in Astyanax, which is uniquely suited for lens manipulations. The first three specific aims are designed to determine the cellular events underlying the arrest of retinal, corneal, and scleral differentiation in cavefish and how the lens modulates these events. In these aims we will combine lens transplantation methods with specific molecular markers for retina, cornea, and sclera development. The fourth specific aim is to identify candidate genes encoding lens-signaling factors affecting the development of other eye parts. The genes will be obtained by a subtractive hybridization using cDNA libraries obtained from isolated surface fish and cavefish lenses. The fifth specific aim is to determine the role of the candidate genes in lens degeneration and lens-regulated development of other eye tissues. This will be done by loss-of-function and gain of function studies, as well as by capitalizing on specific properties of the candidate genes. We expect this research to provide new insights into lens signaling processes and fill a major gap in our understanding of both normal and abnormal eye development.
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