The Physiological Role of the UPF3 Gene Paralogs in Nonsense-Mediated RNA Decay

Nonsense-mediated RNA Decay (NMD) is a post- transcriptional pathway that degrades aberrant mRNAs, as well as up to ̃5% of normal mRNAs. NMD is orchestrated by various factors, including the Upframeshift (UPF) proteins that recognize mRNAs with NMD-inducing features. Of all known factors that participate in NMD, UPF3 is unique in being encoded by two gene paralogs - UPF3A and UPF3B. Loss of UPF3B in humans causes intellectual disability and other neurological disorders. In these patients, as well as other settings in which UPF3B is absent, UPF3A is dramatically upregulated, suggesting that UPF3A compensates for UPF3B. To date, the relationship between these two sister genes and their physiological importance remain elusive.For my dissertation, I elected to study the role of both UPF3A and UPF3B using knockout mouse models. In Upf3b-KO mice, I studied the effect of UPF3B in neuronal development in both the brain and the olfactory epithelium, as well as its downstream effectors in these tissues. I also generated an Upf3a knockout mouse model to study the role of UPF3A in vivo. In the course of my studies, I found that UPF3A, unlike UPF3B, is required for embryonic development. I also discovered that UPF3A is important for spermatogenesis, consistent with the fact that this protein is more highly expressed in the testis than any other adult tissues. Surprisingly, I discovered that while the UPF3A gene is closely related with the UPF3B gene, these two genes have opposing functions. UPF3B promotes NMD, while UPF3A is a NMD inhibitor in several different contexts. Since these two UPF3 proteins are expressed at unequal levels in various tissues, my results suggest that the ratio of these two paralogs dictate the tissue-specific strength of NMD. Together, my research has provided one of the first examples of gene paralogs that have evolved an antagonistic relationship and it has shed light on a unique system to regulate gene expression in a tissue specific and developmentally regulated manne