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

描述(申请人提供)：晶状体的功能依赖于大量少量蛋白质的积累。这些蛋白包括细胞质晶体蛋白、特化膜蛋白和中间丝。三十多年来，人们一直认为，编码这些蛋白质的基因在晶状体纤维细胞的形成过程中被“激活”，晶状体纤维细胞是晶状体的主要组成部分。然而，这项研究中提出的数据表明，编码这些“纤维特异性”蛋白的RNA在晶状体形成的早期就被合成，并存在于晶状体的前体细胞-晶状体上皮细胞中，贯穿整个生命。由于这些mRNA存在，但它们编码的蛋白质不存在，因此必须有机制来确定这些mRNAs在什么时候以及在什么细胞中被翻译成蛋白质。我们的数据表明，这些mRNAs的选择性翻译由称为RNA颗粒(RGS)的蛋白质-RNA复合体控制。我们建议确定晶状体中受转录后机制调控的主要基因，确定调控丰富的晶状体膜蛋白MIP表达所需的RG组分和RNA序列，并确定在晶状体发育过程和出生后生活中负责选择性翻译“纤维细胞特异性”mRNAs的晶状体特异性RG组分。我们希望这些研究将为晶状体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转录后调控的模型。由于晶状体特有的RG成分TDRD7的突变会导致人类白内障，这些研究也将提供关于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.