Specialized ribosomes in control of gene expression and embryonic development

描述（由申请人提供） 摘要：生物学的一个主要挑战是了解基因表达是如何在每分钟的基础上进行调节的，从而产生胚胎发育过程中形成的细胞类型的显着多样性。几十年的研究已经证明，在转录和转录后水平上，基因表达的调控有许多层次，这些层次协调了这一过程。核糖体是一种分子机器，它执行着将基因组表达的所有mRNA翻译成功能蛋白质的艰巨任务。值得注意的是，流行的教条是，核糖体-尽管是一个非常复杂和惊人的机器-在翻译mRNA方面具有组成性而不是调节性功能。我们的研究结果出乎意料地揭示了基因调控和哺乳动物身体计划形成的基本方面是由专门的核糖体功能控制的，该功能指导特定蛋白质产物在何时何地产生。在这里，我们建议全面和系统地测试的假设，““核糖体蛋白质代码””赋予一个新的水平的基因表达调控。为了实现这一目标，我们开发了新的遗传和分子工具，直接在发育中的脊椎动物胚胎中研究翻译控制。我们的研究将描述与核糖体RNA相关的79种不同的核糖体蛋白（RP）如何赋予基于RNA的翻译机制更大的特异性，作为指导转录特异性翻译控制的机制。此外，我们将确定上游，发育调节信号通路，收敛于RP表达和活性的控制，指导核糖体进行更多的翻译控制调节功能。总之，这些研究将描绘一个新的核糖体在体内的基因表达和哺乳动物发育的基本方面是至关重要的调控功能。 公共卫生相关性：在人类中，越来越多的证据将许多核糖体蛋白（RP）的突变与人类疾病联系起来，例如Diamond Blackfan贫血，其特征在于特定组织和细胞类型中的独特病理特征以及癌症易感性。该提案将调查这些RP在控制基因表达方面的知之甚少的功能，这对理解这组人类疾病的病因具有重要意义，并可能有助于引导合理治疗的设计。

DESCRIPTION (Provided by the applicant) Abstract: A major challenge in biology is to understand how gene expression is regulated on a minute-by-minute basis to give rise to the remarkable diversity of cell types that are formed during embryonic development. Decades of research have demonstrated numerous layers in regulation of gene expression, at both the transcription and post-transcription level, which orchestrates this process. Ribosomes are molecular machines that carry out the daunting task of translating all the mRNAs expressed by the genome into functional proteins. Notably, the prevailing dogma has been that the ribosome--although an immensely complex and amazing machine--possesses a constitutive rather than regulatory function in translating mRNAs. Our findings unexpectedly reveal that fundamental aspects of gene regulation and formation of the mammalian body plan are instead controlled by specialized ribosome function that directs where and when specific protein products are made. Here we propose to comprehensively and systematically test the hypothesis that a ""ribosome protein code"" imparts a new level of regulation in gene expression. To accomplish this, we have developed novel genetic and molecular tools to study translational control directly within the developing vertebrate embryo. Our studies will delineate how the 79 distinct ribosomal proteins (RPs) that associate with ribosomal RNA confer greater specificity to the RNA-based translational machinery as a mechanism to direct transcript-specific translational control. In addition, we will identify the upstream, developmentally regulated signaling pathways that converge on control of RP expression and activity, which instruct ribosomes to carry out more regulated functions in translational control. Together, these studies will delineate a novel regulatory function of the ribosome in-vivo that is critically required for fundamental aspects of gene expression and mammalian development. Public Health Relevance: In humans, accumulating evidence links mutations in a number of ribosomal proteins (RPs) to human disease, such as Diamond Blackfan anemia, that is characterized by distinct pathological features in specific tissues and cell types as well as predisposition to cancer. This proposal will investigate the poorly understood functions of these RPs in control of gene expression that has important implications for understanding the etiology of this group of human disorders and may help lead the design of rational therapies.