Characterization of RNA Binding Protein Regulation in Neural Stem Cell Quiescence Exit

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Neurogenesis, the lifelong generation of newborn neurons, occurs in neural stem cell (NSC) niches in the brain. A decline in neurogenesis occurs with aging but also contributes to disease pathologies such as dementia, anxiety and depression. This attenuated neurogenesis is largely the result of the increased barrier to NSC quiescence exit, the process of NSC activation and cell cycle reentry. NSCs dynamically transition between quiescent and activated cell states; quiescent NSCs (qNSCs) are in a reversible G0 state of the cell cycle whereas activated NSCs (aNSCs) divide to self-renew or produce new neurons. Despite quiescence exit being the rate-limiting step in neurogenesis, its mechanisms are not well understood. One key intrinsic mechanism influencing quiescence exit is aggregated protein clearance through the formation of aggresomes which are surrounded by the intermediate filament vimentin. In the absence of vimentin protein, there is decreased qNSC activation both in vivo and in vitro, suggesting that vimentin plays a crucial role in mediating quiescence exit. Interestingly, qNSCs uniquely contain high vimentin mRNA and low protein levels, compared to aNSCs, suggesting that the translational repression of vimentin mRNA in qNSCs is rapidly reversed during quiescence exit to upregulate vimentin protein, facilitating the formation of aggresomes. This indicates that the regulation of vimentin may be uniquely controlled in the transition between cell states. Thus, the identification of the mechanisms underlying this post-transcriptional regulation during quiescence exit will reveal processes that may be targeted to increase neurogenesis. The objective of this proposal is to identify key translational regulators, specifically RNA binding proteins (RBPs), controlling vimentin mRNA translation during NSC quiescence exit. We will characterize RBPs that bind vimentin mRNA preferentially in qNSCs, and establish their functional roles on vimentin mRNA translation, with the eventual goal of correlating post transcriptional mechanisms with the physiologic relevance of enhanced qNSC activation both in vitro and in vivo. Completion of this project will broaden the understanding of the molecular mechanisms underlying qNSC activation and present a potential novel mammalian therapeutic target to increase neurogenesis, with the goals of improving cognitive function with age. In addition to this research, the University of Wisconsin-Madison Medical Scientist Training Program and the Cellular and Molecular Biology graduate program will provide opportunities for advancing my skills in laboratory techniques, responsible conduct of research, professional development, and clinical practice necessary to become a successful independent Physician Scientist.