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.