Understanding Nuclear RNA Quality Control in Mammalian Nervous System

我们基因的表达经过几个精心安排的步骤，包括转录和将初级转录本加工成成熟的信使分子，将信使从细胞核输出到细胞质，并将其翻译成相应的蛋白质产物。这种复杂的过程是精确调节细胞和组织特异性基因表达程序所必需的，而基因表达程序又是生物体正常发育和功能所不可缺少的。相反，基因表达过程中的缺陷与几种人类疾病有关，包括神经和神经精神疾病，如肌强直性营养不良症、脊髓性肌萎缩症、肌萎缩侧索硬化症、额颞叶痴呆，可能还有阿尔茨海默病。这些破坏性疾病与相当大的患者痛苦和死亡率有关，也是国家卫生系统的严重负担。值得注意的是，细胞采用质量控制（QC）机制，通过识别和消除有缺陷的信使分子，可以最大限度地减少错误基因表达的有害影响。细胞QC的一个重要但鲜为人知的分支阻止含有介入性内含子序列的未完全加工的基因转录本从细胞核输出到细胞质，从而阻止它们翻译成异常蛋白质。这种机制在细胞核中保留的转录本最终被消除。本小组和其他人之前的研究表明，除了其错误监视作用外，这种核保留和消除（NRE）途径可能在发育神经系统（NS）的背景下发挥作用，作为一种调节机制，能够对重要的神经元基因进行确定性控制。然而，人类和动物细胞，特别是NS细胞中NRE的分子机制尚不清楚。为此，我们建议使用候选和无偏发现方法相结合的方法来研究哺乳动物的NRE机制。我们还建议研究NRE装置的发育变化及其在NS背景下的生物学后果。为了推进这些研究，我们将结合现有的分子、细胞和发育生物学技术，并将开发创新的实验方法。我们相信，所提出的工作将阐明分子机制，确保我们的基因表达程序的准确性，并开始揭示有助于NS发展和功能的新的基因调控机制。通过阐明这些重要方面，提出的工作也应该提高我们对导致神经性疾病的分子原因的理解，并最终为新的基于知识的治疗和诊断工具铺平道路。

Expression of our genes proceeds through several carefully orchestrated steps including transcription and processing of primary transcripts into mature messenger molecules, export of the messengers from the nucleus to the cytoplasm and their translation into corresponding protein products. This elaborate process is required for precise regulation of cell- and tissue-specific gene expression programmes, which, in turn, is indispensable for proper development and function of the organism. Conversely, defects in gene expression processes have been linked to several human diseases including neurological and neuropsychiatric conditions such as myotonic dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, and possibly Alzheimer's disease. These devastating disorders are associated with considerable patient suffering and mortality as well as a serious burden for the national health system.Notably, cells employ quality control (QC) mechanisms that can minimise deleterious effects of erroneous gene expression by identifying and eliminating defective messenger molecules. An important but poorly understood branch of the cellular QC prevents export of incompletely processed gene transcripts containing intervening intron sequences from the nucleus to the cytoplasm thus preventing their translation into aberrant proteins. Transcripts retained by this mechanism in the nucleus are eventually eliminated. Previous studies by our group and others have suggested that, in addition to its error surveillance role, this nuclear retention and elimination (NRE) pathway may function in the context of developing nervous system (NS) as a regulatory mechanism enabling deterministic control of important neuronal genes. However, molecular mechanisms underlying NRE in human and animal cells in general and NS cells in particular are poorly understood.To this end, we propose to investigate mammalian NRE machinery using a combination of candidate and unbiased discovery approaches. We additionally propose to examine developmental changes in the NRE apparatus and their biological consequences in the NS context. To advance these lines of research, we will use a combination of established molecular, cellular and developmental biology techniques and will additionally develop innovative experimental approaches. We are convinced that the proposed work will shed light on molecular mechanisms ensuring accuracy of our gene expression programme and begin uncovering novel gene regulation mechanisms contributing to NS development and function. By elucidating these important aspects the proposed work should also improve our understanding of molecular causes leading to NS diseases and ultimately pave the way to new knowledge-based therapies and diagnostic tools.