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

描述（由申请人提供）：晶状体的功能依赖于大量少量蛋白质的积累。这些包括细胞质晶体蛋白、特化膜蛋白和中间细丝。三十多年来，人们一直认为编码这些蛋白质的基因在晶状体纤维细胞的形成过程中被“开启”，晶状体纤维细胞构成了晶状体的主体。然而，本研究提出的数据表明，编码这些“纤维特异性”蛋白的rna在晶状体形成早期合成，并在晶状体的祖细胞（晶状体上皮细胞）中存在于整个生命过程中。既然这些mrna存在，但它们编码的蛋白质却不存在，那么一定存在某种机制来决定这些mrna何时以及在哪些细胞中被翻译成蛋白质。我们的数据表明，这些mrna的选择性翻译是由称为RNA颗粒（RGs）的蛋白质-RNA复合物控制的。我们建议鉴定晶状体中受转录后机制调控的主要基因，确定调节丰富晶状体膜蛋白MIP表达所需的RG组分和RNA序列，并鉴定晶状体特异性RG组分，这些RG组分在晶状体发育和出生后生命中负责“纤维细胞特异性”mrna的选择性翻译。我们期望这些研究将定义晶状体基因表达的新范式，并将作为其他组织中基因表达转录后调控的模型。由于晶状体特异性RG成分TDRD7的突变可导致人类白内障，因此这些研究也将为白内障的形成提供基础信息。

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.