SA61 - THE ROLE OF MUSASHI RNA BINDING PROTEINS IN ASSOCIATIVE LEARNING AND MEMORY

Abstract

Background The Musashi family of RNA binding proteins, MSI-1 and MSI-2, retain a pivotal role in stem cell maintenance, nervous system development and tumourigenesis. Recently, we demonstrated that the C. elegans sole ortholog, MSI-1, can regulate forgetting upon associative learning via a 3’ UTR dependent translational repression of the Arp2/3 actin branching complex. Based on these findings, here we opted to decipher the role of human MSI-1 and MSI-2 in the regulation of associative learning and memory; and investigated whether a conserved mechanism of action exists across species. Methods Based on the homology shared between the human and nematode musashi proteins, we first constructed two transgenic C. elegans lines expressing the human proteins in an msi-1 knockout background by using molecular genetic techniques. Moreover, learning and memory (both short-term and long-term) phenotypes were assessed in a paradigm known as negative olfactory chemotaxis assay. Following, using pharmacological manipulations, the function of human musashi proteins were studied both on the molecular and behavioral level. Results Introduction of both human MSI-1 and MSI-2 proteins fully rescued the previously seen forgetting defect of msi-1 (lf) mutant worms, during C. elegans aversive olfactory short-term and long-term memory. Since musashi was shown to regulate gene expression at the translational level via its highly conserved RRM domain, we next sought to disrupt binding to its downstream targets and assessed the effects at the behavioral level. Pharmacological perturbation of both human MSI-1 and MSI-2 function suppressed the memory rescue phenotype previously observed; without causing locomotion, chemotaxis or learning deficits. Discussion Taken together, our results support a conserved role of musashi in negative associative memory from nematodes to humans and might, ultimately, prove to be helpful in elucidating novel therapy targets for the treatment of memory-related disorders.