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

描述（由申请人提供）：透镜的功能依赖于大量适度数量蛋白质的积累。这些包括细胞质晶体蛋白，专门的膜蛋白和中间丝。三十多年来，人们一直认为编码这些蛋白质的基因是在透镜纤维细胞（构成透镜主体的细胞）形成过程中“开启”的。然而，该提案中提供的数据表明，编码这些“纤维特异性”蛋白的RNA在透镜形成的早期合成，并且在整个生命过程中存在于透镜的祖细胞即透镜上皮细胞中。由于这些mRNA存在，但它们编码的蛋白质不存在，因此必须有机制来决定何时以及在什么细胞中这些mRNA被翻译成蛋白质。我们的数据表明，这些mRNA的选择性翻译是由蛋白质-RNA复合物称为RNA颗粒（RGs）。我们建议确定的主要基因，调节在透镜的转录后机制，确定RG组件和RNA序列需要调节丰富的透镜膜蛋白，MIP的表达，并确定透镜特定的RG组件，负责整个透镜发展和出生后的生活中的“纤维细胞特异性”mRNA的选择性翻译。我们期望这些研究将为透镜基因表达定义一个新的范例，并将作为其他组织中基因表达的转录后调控模型。由于晶状体特异性RG成分TDRD 7的突变会导致人类白内障，因此这些研究还将提供有关白内障形成的基本信息。

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.