Elucidating the neural specific functions of the RNA-binding protein Caper in neural development and neurodegeneration

项目总结/摘要 转录后基因调控是一种基本的机制，有助于调节发育， 神经系统的健康老化。破坏RNA结合蛋白（RBP）功能的突变， 调节转录后基因调控，越来越多地涉及神经系统疾病 包括肌萎缩侧索硬化症、脆性X综合征和脊髓性肌萎缩。有趣的是， 尽管大多数RBP在不同的组织类型中广泛表达，但神经系统通常 对他们的功能障碍特别敏感。这个项目的长期目标是开始阐明如何 由普遍表达的RBP功能障碍引起的RNA调节异常，导致组织 神经系统疾病背后的特殊病理为此，高度保守的剪接因子Caper 将被用作模型。Caper在整个开发过程中广泛表达， 果蝇感觉和运动神经元的发育。此外，跳跃功能障碍会导致 神经变性并导致成年运动缺陷。虽然我们对它的功能知之甚少， 人刺山柑同源基因RBM 39，它在神经系统内表达，表明其神经功能可能 要保守。本申请中提出的研究将测试Caper调节RNA的假设 通过参与特异性核糖核蛋白复合物， （RNP）在神经系统中。我们已经确定了编码RBP的蛋白质，它们只与Caper相互作用。 在脑内，沿着神经特异性Caper靶RNA。使用高度易处理的模型，果蝇， 组织特异性分子遗传操作将与生物化学结合使用， Caper与这些RBP组合发挥作用以指导神经发生和保护衰老的程度 大脑神经退化此外，我们将进一步表征神经退行性表型 以确定哪些细胞类型正在老化的大脑中经历细胞死亡。 由于异常的RNA调节已经成为各种神经退行性疾病和 神经发育障碍，从这项研究中获得的知识具有广泛的意义， 和治疗神经系统疾病

Project Summary/Abstract Post-transcriptional gene regulation is a fundamental mechanism that helps regulate the development and healthy aging of the nervous system. Mutations that disrupt the function of RNA-binding proteins (RBPs), which regulate post-transcriptional gene regulation, have increasingly been implicated in neurological disorders including amyotrophic lateral sclerosis, Fragile X Syndrome, and spinal muscular atrophy. Interestingly, although the majority of RBPs are expressed widely within diverse tissue types, the nervous system is often particularly sensitive to their dysfunction. The long-term goal of this project is to begin to elucidate how aberrant RNA regulation that results from the dysfunction of ubiquitously expressed RBPs, leads to tissue specific pathologies that underlie neurological diseases. To this end, the highly conserved splicing factor Caper will be used as a model. Caper is widely expressed throughout development and is required for the development of Drosophila sensory and motor neurons. Furthermore, caper dysfunction causes neurodegeneration and results in adult locomotor deficits. Though little is known about the function of the human caper ortholog, RBM39, it is expressed within the nervous system suggesting its neural functions may be conserved. The research proposed within this application will test the hypothesis that Caper regulates RNA targets in a combinatorial manner within neuronal cells by participating in specific ribonucleoprotein complexes (RNPs) within the nervous system. We have identified proteins encoding RBPs that interact with Caper only within the brain, along with neural specific Caper target RNAs. Using the highly tractable model, Drosophila, tissue specific molecular genetic manipulations will be used in conjunction with biochemistry to determine the extent to which Caper functions combinatorially with these RBPs to direct neurogenesis and protect the aging brain from neurodegeneration. Furthermore, we will further characterize the neurodegenerative phenotypes associated with caper dysfunction to determine which cell types are undergoing cell death in the aging brain. Since aberrant RNA regulation has emerged as a common theme in various neurodegenerative and neurodevelopmental disorders, the knowledge gained from this study has broad implications for understanding and treating neurological disorders.