Inhibition of Cpeb3 ribozyme elevates CPEB3 protein expression and polyadenylation of its target mRNAs, and enhances object location memory
- University of California, Irvine, United States
- University of Queensland, Australia
- Ionis Pharmaceuticals, United States
Abstract
A self-cleaving ribozyme that maps to an intron of the cytoplasmic polyadenylation element binding protein 3 (Cpeb3) gene is thought to play a role in human episodic memory, but the underlying mechanisms mediating this effect are not known. We tested the activity of the murine sequence and found that the ribozyme’s self-scission half-life matches the time it takes an RNA polymerase to reach the immediate downstream exon, suggesting that the ribozyme-dependent intron cleavage is tuned to co-transcriptional splicing of the Cpeb3 mRNA. Our studies also reveal that the murine ribozyme modulates maturation of its harboring mRNA in both cultured cortical neurons and the hippocampus: inhibition of the ribozyme using an antisense oligonucleotide leads to increased CPEB3 protein expression, which enhances polyadenylation and translation of localized plasticity-related target mRNAs, and subsequently strengthens hippocampal-dependent long-term memory. These findings reveal a previously unknown role for self-cleaving ribozyme activity in regulating experience-induced co-transcriptional and local translational processes required for learning and memory.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1 - 7.
Article and author information
Author details
Luiz F M Passalacqua
Funding
National Institutes of Health (R01AG051807)
- Marcelo A Wood
National Institutes of Health (RF1AG057558)
- Marcelo A Wood
National Science Foundation (1804220)
- Andrej Luptak
National Science Foundation (1330606)
- Andrej Luptak
National Science Foundation Graduate Research Fellowship Program
- Claire C Chen
National Institutes of Health (R01CA229696)
- Claire C Chen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Anne E West, Duke University, United States
Ethics
Animal experimentation: All experimental procedures were performed according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of the University of California, Irvine.
Version history
- Preprint posted: June 9, 2023 (view preprint)
- Received: June 13, 2023
- Accepted: February 5, 2024
- Accepted Manuscript published: February 6, 2024 (version 1)
- Version of Record published: March 7, 2024 (version 2)
Copyright
© 2024, Chen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Inhibition of Cpeb3 ribozyme elevates CPEB3 protein expression and polyadenylation of its target mRNAs, and enhances object location memory
eLife 13:e90116.
https://doi.org/10.7554/eLife.90116
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