Cytoplasmic polyadenylation is a prominent and evolutionarily conserved mechanism to regulate mRNA translation. Poly(A) length control is mediated by several factors including the RNA binding protein CPEB1, the non-canonical poly(A) polymerase Gld2, the deadenylating enzyme PARN, and the multi-protein complex CPSF. Current models indicate that CPEB1 binds the 3'UTR cytoplasmic polyadenylation element (CPE), which anchors the other proteins to RNA. PARN activity is robust and shortens the poly(A) tail, leading to translational inactivation. Upon signal-induced CPEB1 phosphorylation, PARN is expelled from the complex allowing Gld2 to catalyze polyadenylation by default, which in turn induces translation. These and other polyadenylation factors reside in neuronal dendrites where, upon synaptic stimulation, they promote polyadenylation-induced translation and resulting synaptic plasticity, the underlying cellular basis for learning and memory. Indeed. CPEB1 ablation in the brain results in synaptic impairment and behavioral deficiencies. Surprisingly, Gld2 ablation has no observable effect on animal behavior. However, a second non-canonical poly(A) polymerase, Gld4, which like Gld2 is tethered to RNA by CPEB1 but regulates the polyadenylation of different sets of mRNAs, is also present in the brain. Stereotactic injection of AAV9 vectors expressing shRNAs for Gld2 or Gld4 into the hippocampus of mice elicits little change in animal behavior. However, a double depletion of both Gld2 and Gld4 results in robust changes in behavior. These data suggest that the combination of Gld2 and Gld4 are necessary for cognitive function. We will dissect the mechanisms by which these two RNA modifying enzymes regulate mRNA metabolism and how they control neural function. This work will take the bottom-up approach of dissecting molecular mechanism, but will also help define how the brain utilizes polyadenylation and translational control to maintain proper synaptic efficacy. This work has important implications for brain activity, particularly learning and memory, and diseases associated with impairment of higher cognitive function.
The maintenance of protein homeostasis in the brain is essential for normal cognitive function. A number of factors regulate mRNA translation in the brain, two of which are the RNA modifying enzymes Gld2 and Gld4. Our work will dissect how these two factors regulate translation, and by so doing, how they promote synaptic plasticity and normal animal behavior.
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