# Polyadenylation and Translational Control

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $367,244

## Abstract

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.

## Key facts

- **NIH application ID:** 9856445
- **Project number:** 5R01GM046779-27
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Joel D Richter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $367,244
- **Award type:** 5
- **Project period:** 1992-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856445

## Citation

> US National Institutes of Health, RePORTER application 9856445, Polyadenylation and Translational Control (5R01GM046779-27). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9856445. Licensed CC0.

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