Polyadenylation induced translation in the brain

Brown University, Providence RI

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Abstract

Long-term changes in synaptic efficacy may regulate the regulated translational of dendritic mRNAs. Although a number of mechanisms may be responsible for such regulation, one that appears to be involved is cytoplasmic polyadenylation. This process occurs during the early development of probably most metazoans, and controls the translation of several maternal mRNAs that are necessary for oocyte maturation and body plan formation. Two cis elements in the 3' untranslated region of responding mRNAs are necessary for polyadenylation, the U-rich cytoplasmic polyadenylation element (CPE) and the near-ubiquitous hexanucleotide AAUAAA. The CPI is bound by the sequence-specific RNA binding protein CPEB, which is essential for polyadenylation. In addition to oocytes, CPEB is found in the brain, and is particularly enriched in the hippocampus, visual cortex and Purkinje cells of the cerebellum. More specifically, CPEB is found at synapses, and co- purifies with the postsynaptic density. CaMKII mRNA, which is important for long term memory storage, contains CPEs within its 3' untranslated region, and these are bound by CPEB. -CaMKII mRNA also undergoes experience-dependent polyadenylation and translation, suggesting that its expression is controlled by CPEB. Here, the molecular function of CPEB in the brain will be explored. An analysis of possible CPEB involvement in mRNA localization to dendrites will be conducted. Dominant negative CPEB mutant proteins will be employed to determine the importance of this molecule in mRNA polyadenylation and translation. The yeast two-hybrid assay will be used to identify CPEB interacting proteins in the brain. A cDNA library enriched for sequences that undergo polyadenylation in response to synaptic stimulation will be constructed. Finally, a mouse line with a brain-specific deletion of the CPEB gene will be generated. These experiments will have important implications for the underling basis of learning and memory.