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Review
. 2023 Jul;28(7):2728-2736.
doi: 10.1038/s41380-023-02088-x. Epub 2023 May 2.

CPEB and translational control by cytoplasmic polyadenylation: impact on synaptic plasticity, learning, and memory

Yi-Shuian Huang #  1 , Raul Mendez #  2   3 , Mercedes Fernandez  4 , Joel D Richter  5
Affiliations
Review

CPEB and translational control by cytoplasmic polyadenylation: impact on synaptic plasticity, learning, and memory

Yi-Shuian Huang et al. Mol Psychiatry. 2023 Jul.

Abstract

The late 1990s were banner years in molecular neuroscience; seminal studies demonstrated that local protein synthesis, at or near synapses, was necessary for synaptic plasticity, the underlying cellular basis of learning and memory [1, 2]. The newly made proteins were proposed to "tag" the stimulated synapse, distinguishing it from naive synapses, thereby forming a cellular memory [3]. Subsequent studies demonstrated that the transport of mRNAs from soma to dendrite was linked with translational unmasking at synapses upon synaptic stimulation. It soon became apparent that one prevalent mechanism governing these events is cytoplasmic polyadenylation, and that among the proteins that control this process, CPEB, plays a central role in synaptic plasticity, and learning and memory. In vertebrates, CPEB is a family of four proteins, all of which regulate translation in the brain, that have partially overlapping functions, but also have unique characteristics and RNA binding properties that make them control different aspects of higher cognitive function. Biochemical analysis of the vertebrate CPEBs demonstrate them to respond to different signaling pathways whose output leads to specific cellular responses. In addition, the different CPEBs, when their functions go awry, result in pathophysiological phenotypes resembling specific human neurological disorders. In this essay, we review key aspects of the vertebrate CPEB proteins and cytoplasmic polyadenylation within the context of brain function.

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The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Illustrations of methods for poly(A) length measurement.
a Transcript-specific measurement. PCR-based polyadenylation test (PAT) and ligation-mediated PAT (LM-PAT) use an adaptor-oligo(dT) primer for reverse transcription (RT), followed by ± the oligo(dT) ligation step and then PCR-amplification of the target transcript. To validate that the mobility shift on a Northern blot is due to poly(A) lengthening, removal of poly(A) by oligo(dT) and RNaseH can be applied. b Transcripts with varying poly(A) lengths are eluted from oligo(dT) or poly(U) beads under increasing temperature or salt concentration and then identified by microarray or next-generation sequencing (NGS). c Illumina platforms. PAL-seq and TAIL-seq use 4 similar steps to prepare samples for NGS. PAL-seq uses biotin-dUTP incorporation and streptavidin-labeled fluorescence to estimate the poly(A) length on a customized platform. TAIL-seq uses a customized algorithm for base calling at 3′ termini of cDNAs. d PacBio single molecular real-time (SMRT) sequencing. FLAM-seq and PAIso-seq use different ways to extend a few nucleotides after the poly(A) tail, followed by RT and GC-paired template switching to add a 5′-adaptor. After PCR and adaptor ligation, the library prepared by SMRTbell technology is used for long-read sequencing. e Nanopore sequencing. After adding the 3′-adaptor and RT, the RNA-DNA hybrid is ligated with a proprietary motor adaptor and guided into the nanopore. As the RNA is unwound, it moves through the nanopore; base calling depends on the characteristics of the electrical current that is applied to the nanopore cassette.
Fig. 2
Fig. 2. Model of CPEB-mediated mRNA repression coupled to dendritic localization followed by local activation.
CPEBs form repression liquid-like droplets (LLDs) stabilized by their N-terminal IDRs. These coacervates include, in addition to CPE-containing transcripts, deadenylation machinery (such as CCR4/Not or PARN), and 5′ cap-blocking factors (such as Maskin or Neuroguidin), which maintain mRNA silencing during transport. CPEBs associate with microtubule motors (kinesins and dyneins). In response to synaptic stimulation likely NMDAR signaling, LLDs are dissolved and CPEB co-factors remodeled. Cap-blocking proteins and deadenylases dissociate and atypical poly(A) polymerases (GLD2/4) promote poly(A) tail elongation and subsequent stabilization of the PABP-eiF4G-eiF4E complex, which in turn locally activates translation of CPE-containing mRNAs.
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