POST TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION IN THE LENS (LENS GENE EXPRESSION

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DESCRIPTION (provided by applicant): The lens depends for its function on the accumulation of large amounts of a modest number of proteins. These include cytoplasmic crystallins, specialized membrane proteins and intermediate filaments. For more than thirty years it has been assumed that the genes encoding these proteins are "turned on" during the formation of lens fiber cells, the cells that make up the bulk of the lens. However, the data presented in this proposal show that the RNAs encoding these "fiber-specific" proteins are synthesized early in lens formation and are present in the progenitor cells of the lens, the lens epithelial cells, throughout life. Since these mRNAs are present, but the proteins that they encode are not, there must be mechanisms that determine when and in what cells these mRNAs are translated into protein. Our data suggest that selective translation of these mRNAs is governed by protein-RNA complexes called RNA granules (RGs). We propose to identify the major genes that are regulated in the lens by post-transcriptional mechanisms, determine the RG components and RNA sequences required to regulate the expression of an abundant lens membrane protein, MIP, and to identify the lens-specific RG components that are responsible for the selective translation of the "fiber cell-specific" mRNAs throughout lens development and in postnatal life. We expect that these studies will define a new paradigm for lens gene expression and will serve as a model for post-transcriptional regulation of gene expression in other tissues. Since mutation of one lens-specific RG component, TDRD7, causes human cataracts, these studies will also provide fundamental information about cataract formation.