The role of the nonsense mediated RNA decay pathway in regulating cell fate

University Of California, San Diego, La Jolla CA

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Abstract

? DESCRIPTION (provided by applicant): The mechanisms dictating whether a cell proliferates or differentiates are fundamental to cellular development, but remain poorly understood. This proposal focuses on a RNA degradation pathway, known as nonsense mediated decay (NMD), as a post-transcriptional mechanism driving the balance between cell proliferation and differentiation. NMD was originally identified as a quality control mechanism for degrading aberrant transcripts harboring premature stop codons and was recently found to also regulate the expression of normal transcripts. Disruption of components in the NMD pathway lead to developmental defects in species ranging the phylogenetic scale, however, it is unclear what role NMD has in developmental processes. Recently, the Wilkinson laboratory has established a role for NMD in regulating the stem cell and neurogenic programs in mice. This regulation occurs in part through NMD degrading messages encoding proteins involved in neural differentiation. Given that loss of function mutations in the NMD factor gene UPF3B, cause intellectual disability in humans, these findings suggest that NMD may be important for proper brain development. Accordingly, the first aim of this proposal is to determine how the NMD pathway contributes to the neural stem and differentiated cell programs in humans. This will be achieved by determining how the magnitude of NMD changes during neural progenitor cell differentiation and maturation, and how knock-down and over-expression of NMD factors influences the fate of human neural progenitor cells. Further, direct targets of NMD will be identified, which will establish the pathways that NMD regulates in neural development. It is known that NMD factor levels vary in different tissues, cell types and developmental states, but in most cases the underlying mechanism behind these changes is unclear. Accordingly, aim two of this proposal is dedicated to investigating the mechanisms governing NMD factor levels. This will be achieved by scrutinizing both transcriptional and post-transcriptional processes that alter NMD factor levels. Together, the results from these two aims will further our understanding of the role NMD in development and will have implications for human diseases arising from defects in NMD.