Dr. Peter Stoilov

Post-transcriptional regulation of gene expression by Musashi proteins

The Musashi proteins are a family of RNA binding proteins that are conserved across metazoans. They were first described as stem cell maintenance factors in Drosophila, a function that is also conserved in vertebrates. Molecularly, the Musashi proteins are reported to promote or repress protein translation through various and at times mutually exclusive mechanisms. Mammals possess two orthologous copies of the Musashi egen - Msi1 and Msi2. We showed that in contrast to their originally described role in stem cell maintenance, the highest level of expression of both Msi1 and Msi2 in mammals is in the terminally differentiated photoreceptor cells. There the Musashi proteins are required for the function and survival of photoreceptors. We show that in photoreceptors the Musashi proteins regulate alternative pre-mRNA splicing and protein expression. Our current research aims to determine how the Musashi proteins regulate splicing and protein expression, and how individual targets of Musashi regulation support photoreceptor function. In the course of this research we have stumbled upon two paradoxical phenomena: evolutionary conserved exons with no detectable function and Musashi controlled global post-transcriptional changes in protein expression that are not due to changes in mRNA levels or translational efficiency. These unexpected outcomes raise interesting questions about the mechanisms of natural selection and protein expression.