Translational Control of Neuronal MRNAs

Download or read book Translational Control of Neuronal MRNAs written by Tatiana Nevarko and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The processes of learning and memory require accurate translational control of neuronal mRNAs. This control can be carried out through the regulation of the general translation machinery and upstream factors, as well as through the recognition and selective translation of specific mRNAs. In this work we explore two molecular mechanisms of translational control in neurons. First, we investigate the roles of RNA helicases eIF4A1 and DHX29 in controlling the translation of synaptically-localized mRNAs. We demonstrate the preferential translation of mRNAs with extensively structured 5'UTR, underlining the importance of this region in translational control. We also pinpoint the post-synaptic localization of DHX29 and propose a technique for monitoring the rate of 5'UTR-dependent translation in vivo with the use of a photoconvertible fluorescent reporter protein. Second, we study the role of cap-dependent translation in autism spectrum disorders (ASD) by examining translationally controlled mRNAs. We show that knockout of eIF4E binding protein 2 (4E-BP2, eIF4E repressor downstream of mTOR) or overexpression of eIF4E in mice lead to increased translation of neuroligin mRNAs, which can explain the autistic-like behaviours in these mice. Moreover, we design short hairpin RNAs packaged in lentiviral particles to modulate the expression of neuroligins in vivo. We use this technology to validate the mechanism of dysregulated neuroligin mRNA translation as the causal factor for the autism-like behaviour in the 4E-BP2 knockout mice. Finally, we propose a mechanism for the exaggerated translation of neuroligin mRNAs through their 5'UTRs. In conclusion, in this work we provide evidence that translational control of specific brain mRNAs is crucial for synaptic function and behaviour." --