The role of Translation in Wnt mediated spine morphogenesis. (360G-Wellcome-087258_Z_08_A)

This project aims to examine the effect of Wnt signalling in protein translation during the formation of dendrites spines, excitatory postsynaptic structures, in the hippocampus. Changes in spines have been observed during long-term plasticity. Moreover, loss of spines has been associated with disorders like autism, schizophrenia and in neurodegenerative diseases. Our new studies reveal for the first time that Wnt7a, a member of the Wnt family expressed in the hippocampus, stimulates the formation of excitatory synapses with no significant effect of inhibitory synapses. Through gain and loss of function studies, we demonstrated that Wnt7a stimulates the formation and growth of spines. Postsynaptically Wnt signalling stimulates the maturation of dendritic spines in the hippocampus through a mechanism that involves Dishevelled-I (Dvll), a scaffold protein that regulates local Wnt signalling. To begin to understand the mechanism by which Wnt signalling regulates spine morphogenesis we performed a yeast two-hybrid screen to look for Dvll interactors. In this screen we identified Microspherules Protein 58 (MSP58), a novel RNA-binding protein that interacts with fragile X mental retardation protein (FMRP). Interestingly, FMRP has been implicated in spine morphogenesis by regulating local translation. In addition, FMRP binds to microRNAs. These findings suggest the interesting possibility that Wnt-Dvl signaling could regulate local translation through MSP58 and FMRP. In this project, the student will examine: I) The role of translation in Wnt mediated spine morphogenesis. 2) The role of MSP58 and FMRP in spine development and their contribution to Wnt-mediated spin morphogenesis. 3) The function ofmicroRNAs in Wnt-mediated function of spine formation and growth.