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CHARACTERIZATION OF NEURONAL CELL-SPECIFIC RNA-BINDING PROTEINS IN THE DEVELOPMENT OF RETINA

视网膜发育过程中神经细胞特异性 RNA 结合蛋白的表征

基本信息

批准号：
15591849
负责人：
KIKUCHI Takanobu
金额：
$ 2.24万
依托单位：
SHINSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Neuronal RNA-binding proteins play an important role in post-transcriptional regulation of gene expression such as alternative splicing, RNA transport and local translation. Several families of neuronal RNA-binding proteins have been so far described. For example, Hu proteins have been identified as an autoantigen of human paraneoplastic encephaloneuropathies associated with lung small cell carcinomas. One of the major functions of Hu proteins is regulation of mRNA metabolism through binding to RNA stability elements. Nova-1, known as the paraneoplastic opsoclonus-myoclonus ataxia antigen, is also a neuron-specific RNA binding protein that regulates alternative splicing. Recently, we have cloned a homologue of PTB as a possible autoantigen of cancer-associated retinopathy from human and rat cDNA libraries. This new protein was named as PTB-like protein (PTBLP).In this study, the possible roles of PTBLP on neuronal differentiation were examined using PC12 cells and PTBLP null mice. Duri … More ng NGF-induced neuronal differentiation in PC12 cells, PTBLP-L (long form) was down-regulated. By transfection of PTBLP-L into PC12 cells, the neuronal differentiation was suppressed. In PTBLP-S (short form ; lack the RNA binding ability) transfected cells, however, this suppression was not evident. When both PTBLP-L and PTBLP-S were co-transfected, the suppressive effect of PTBLP-L decreased. In differentiated cells, PTBLP-S localized in the nucleus and PTBLP-L was found dispersed throughout the cytoplasm and neuronal growth cone. These findings suggest that PTBLP-L acts as a negative regulator of neuronal differentiation and PTBLP-S acts as a competitor of PTBLP-L. To explore the functions of PTBLP in the intact animal, we undertook to knock out the PTBLP gene in mice by homologous recombination. PTBLP null mice were died in embryonic late stage. There was no abnormal phenotype in PTBLP heterozygotes. Those results are suggested that PTBLP may play an important role in neuronal development. Less

神经元RNA结合蛋白在基因表达的转录后调控中发挥重要作用，如选择性剪接、RNA转运和局部翻译等。迄今为止，已经描述了几个神经元RNA结合蛋白家族。例如，Hu蛋白已被鉴定为与肺小细胞癌相关的人类副肿瘤性脑神经病的自身抗原。Hu蛋白的主要功能之一是通过与RNA稳定元件结合来调节mRNA代谢。Nova-1，被称为副肿瘤性眼阵挛-肌阵挛共济失调抗原，也是一种调节选择性剪接的神经元特异性RNA结合蛋白。最近，我们已经从人类和大鼠cDNA文库中克隆了PTB的同源物，其可能是癌症相关视网膜病变的自身抗原。本研究利用PC 12细胞和PTBLP基因敲除小鼠研究了PTBLP在神经元分化中的作用。杜里 ...更多信息 ng NGF诱导的PC 12细胞神经元分化中，PTBLP-L（长型）下调。通过转染PTBLP-L到PC 12细胞中，神经元分化受到抑制。然而，在PTBLP-S（短形式;缺乏RNA结合能力）转染的细胞中，这种抑制不明显。当PTBLP-L和PTBLP-S共转染时，PTBLP-L的抑制作用减弱。在分化的细胞中，PTBLP-S定位于细胞核，PTBLP-L被发现分散在整个细胞质和神经生长锥。这些结果表明，PTBLP-L作为神经元分化的负调节剂和PTBLP-S作为PTBLP-L的竞争者。为了研究PTBLP在动物体内的功能，我们采用同源重组的方法敲除小鼠PTBLP基因。PTBLP基因敲除小鼠在胚胎晚期死亡。PTBLP杂合子无异常表型。这些结果表明PTBLP可能在神经元发育中起重要作用。少