Nxf1 is the modifier of vibrator: Altering gene expression through mRNA export

Nuclear export is a vital step in eukaryotic gene expression. Pre-messanger RNA (pre-mRNA) is transcribed in the nucleus and must be properly processed before it is exported to the cytoplasm, where it is translated into protein by the ribosomes. To insure efficiency and accuracy in this process, these steps of transcription, mRNA processing, and export are coupled together through protein-protein interactions. Coupling of sequential steps has recently been the subject of several interesting studies and intense debate. An additional link from export to processing is apparent through my studies on the retrovirus insertional mutant, vibrator. The vibrator mutation is an allele of phosphatidylinositol transfer protein (Pitpn ) with an insertion of an endogenous retrovirus, intracisternal A particle (IAP), into the fourth intron of the gene. This insertion results in a decrease in expression of the gene to about 20% of wild-type levels and production of an apparently short-lived, aberrantly processed message. Mice that homozygous for the vibrator mutation suffer from severe, juvenile-onset action tremor; neurodegeneration in the brainstem and spinal cord; and early death. The CAST/Ei allele of Modifier of vibrator 1 (Mvb1) ameliorates these phenotypes by increasing the levels of Pitpn gene expression and decreasing the amount of aberrant message. These mice have a less severe tremor, do not show obvious neurodegeneration, and have extended life spans. The same genetic locus also modifies at least one other retrovirus insertional mutation, Eya1 BOR. I have found through in vivo and in vitro complementation that the gene that is responsible for this suppression is the mRNA export receptor, Nxf1. Further, I have shown through in vitro complementation with virally expressed Nxf1 that the amino acid change that causes the suppression is E610G, a naturally-occurring polymorphism in a C-terminal ubiquitin associated domain that binds to the nuclear pore complex. These findings provide an intriguing retrograde link between mRNA export and mRNA processing.