Interdisciplinary Graduate Program, MD/PhD
First Thesis Advisor
CNOT7, deadenylation, polyadenylation, local translation, synaptic plasticity
Local translation of mRNAs in dendrites is vital for synaptic plasticity and learning and memory. Tight regulation of this translation is key to preventing neurological disorders resulting from aberrant local translation. Here we find that CNOT7, the major deadenylase in eukaryotic cells, takes on the distinct role of regulating local translation in the hippocampus. Depletion of CNOT7 from cultured neurons affects the poly(A) state, localization, and translation of dendritic mRNAs while having little effect on the global neuronal mRNA population. Following synaptic activity, CNOT7 is rapidly degraded resulting in polyadenylation and a change in the localization of its target mRNAs. We find that this degradation of CNOT7 is essential for synaptic plasticity to occur as keeping CNOT7 levels high prevents these changes. This regulation of dendritic mRNAs by CNOT7 is necessary for normal neuronal function in vivo, as depletion of CNOT7 also disrupts learning and memory in mice. We utilized deep sequencing to identify the neuronal mRNAs whose poly(A) state is governed by CNOT7. Interestingly these mRNAs can be separated into two distinct populations: ones that gain a poly(A) tail following CNOT7 depletion and ones that surprisingly lose their poly(A) tail following CNOT7 depletion. These two populations are also distinct based on the lengths of their 3’ UTRs and their codon usage, suggesting that these key features may dictate how CNOT7 acts on its target mRNAs. This work reveals a central role for CNOT7 in the hippocampus where it governs local translation and higher cognitive function.
McFleder, RL. Regulation of Local Translation, Synaptic Plasticity, and Cognitive Function by CNOT7. (2017). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 915. DOI: 10.13028/M2KM3R. https://escholarship.umassmed.edu/gsbs_diss/915
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Available for download on Friday, August 23, 2019