Mechanisms regulating ribosome assembly and function in stem cells and vertebrate development.

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Protein synthesis underpins a cell’s decision to growth, proliferate and/or differentiate.2,6,11–14,14,15,18 Understanding how protein synthesis allow cells to perform these fundamental activities is a major challenge in biology. Therefore, there is a critical need to elucidate the mechanisms determining protein synthesis rates and whether these mechanisms operate in a cell type-specific manner to impart a new layer of regulation in the control of gene expression. To explore these questions, two orthogonal, but complementary, research programs, namely Program 1 and 2, have been designed. Program 1 investigates new factors and mechanisms involved in the regulated assembly of ribosomes in stem cells. Program 1 is built upon recent studies from my lab and others demonstrating that stem cells relies on ribosome assembly to ensure adequate protein synthesis rates and the transition from self-renewal to differentiation.2,3,6,11–14,14,15,18 My lab has characterized the composition of the small subunit (SSU) processome in human cells, and identified DNA-dependent protein kinase (DNA-PK) as an RNA-dependent regulator of ribosome assembly and proteins synthesis in hematopoietic stem cells.6 Thus, the immediate goal of Program 1 is to establish the mechanisms by which DNA-PK regulates ribosome biogenesis in stem cells. Program 2 explores how customizing ribosome assembly and function contributes to protein synthesis and selective mRNA translation during embryogenesis. Program 2 is underscored by recent findings suggesting that ribosomes composition and activity are dynamically regulated in a cell type- and tissue- specific manner, allowing protein expression to be regulated with exquisite temporal and spatial precision.8,12 The immediate goal of Program 2 is to generate in vivo model systems to understand how the cell creates and regulates ribosome heterogeneity and the importance of this form of regulation for proper cellular function and organismal development. To address these, we have generated transgenic zebrafish in which two compositionally distinct and developmentally regulated ribosomes have been genetically labeled, a unique and powerful tool to study functional aspects of the ribosome in an in vivo developmental model system. Over the next five years, we expect Program 1 and 2 to uncover new mechanisms regulating ribosomes assembly and function in stem cells and vertebrate development and to provide powerful insights into ribosomopathies, tissue- specific disorders linked to defects in ribosome biogenesis and function.