Photoreceptors are a highly specialized type of neuron with extraordinary properties. Rod photoreceptors are exquisitely sensitive to light due to their precise and unique morphology as well as their highly efficient phototransduction mechanism. They are also the cell type that seems most vulnerable to degeneration in that many genetic and environmental lesions lead to their degeneration. We propose to study the mechanisms of genesis and differentiation of murine rod photoreceptors. Over the last grant period, we characterized the response of retinal cells to two extrinsic cues that negatively and positively regulate rod development, ciliary neurotrophic factor (CNTF) and taurine, respectively. We also characterized a role for the retinal anterior homeobox gene, Rax, in photoreceptor development. We have been developing reagents to probe the molecular consequences of the action of these extrinsic factors and the Rax gene. In addition, we discovered that a number of newly characterized genes are expressed during retinal development in a manner that is highly suggestive of a role in rod development. We pioneered the application of two new techniques, electroporation and RNAi, for rapid manipulation of gene expression levels in the retina in vivo. These new methods, along with the knowledge of many new genes that serve as markers of the rod pathway, will greatly aid in the study of gene function in the development of rod photoreceptors. Our goal is to create a molecular description of the pathway of rod development, including the series of gene expression changes that occur in the pathway, and place the action of the regulators of rod development within this pathway.
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