In recent years, the role of RNA-binding proteins in gene expression regulation has become increasingly prominent. The CPEB (cytoplasmic polyadenylation element binding protein) family, as core proteins regulating mRNA translation, localization, and stability, is emerging as a hotspot in neuroscience and translational medicine research due to its critical roles in synaptic plasticity, long-term memory formation, and various neuropsychiatric disorders. CPEB family members, especially their unique prion-like domains, provide a novel perspective for understanding the mechanisms of memory persistence and treating related diseases. This article will systematically elaborate on the functional mechanisms of the CPEB family and their central roles in the nervous system, from development and functional maintenance to the pathogenesis of diseases.
 

The CPEB Target: A Critical Node in the Gene Expression Regulatory Network
 

The CPEB family is a class of crucial sequence-specific RNA-binding proteins, comprising four core members in vertebrates: CPEB1, CPEB2, CPEB3, and CPEB4. They bind to cytoplasmic polyadenylation elements in the 3'UTR of target mRNAs via C-terminal RNA recognition motifs and regulate translation by controlling the length of their polyadenylation tails.
 

Members exhibit overlapping yet highly specific tissue distribution, regulatory mechanisms, and functions:
 

CPEB1, as a key translational activator, plays a central role in gametogenesis, neuronal synaptic plasticity, and cell cycle regulation.
 

CPEB2, CPEB3, and CPEB4​ form a subfamily, with N-terminal containing unique prion-like domains.
 

CPEB3​ is widely expressed in the central nervous system and is essential for hippocampal-dependent long-term memory formation. Its prion-like aggregation properties serve as the physical basis for achieving synapse-specific, long-lasting enhancement of protein synthesis.
 

CPEB4​ is involved in stress responses and disease processes. For instance, it translocates to the nucleus under hypoxic conditions to regulate adaptive gene expression. Its dysregulation is associated with autism spectrum disorder and tumor angiogenesis.
 

In summary, the CPEB family, through the differential expression and unique regulatory patterns of its members, constitutes a precise and multi-layered gene expression regulatory network.
 

Nervous System Development: A Precise Navigation System for mRNA Spatiotemporal Localization
 

During nervous system development, CPEB proteins, as key regulators, precisely guide cell fate and morphogenesis through the spatiotemporal localization and local translation of mRNAs. For example, in the asymmetric division of Drosophila neuroblasts, the CPEB homolog Orb2 recognizes and guides aPKC mRNA to the apical cell region for local synthesis, establishing cell polarity and ensuring proper spindle orientation. In vertebrate neuronal growth cone development, CPEB1 binds to mRNAs such as β-catenin, transports them to the leading edge of the growth cone, and initiates local translation upon activation by external signals, regulating cytoskeletal rearrangement to guide axon growth. Concurrently, CPEB1's translational regulation of mRNAs related to mitochondrial function (e.g., complex I subunits) provides the necessary energy support for this highly energy-consuming process, ensuring normal neuronal morphogenesis.

 

Figure source: The role of CPEB family proteins in the nervous system function in the norm and pathology
 

Memory Formation Mechanism: A Persistent Translational Switch for Synapse Specificity
 

The core mechanism of CPEB in long-term memory formation lies in its precise regulation of local protein synthesis at synapses. Upon repeated synaptic stimulation, CPEB3 undergoes rapid deSUMOylation, transitioning from a translation-inhibitory monomeric state to functional amyloid-like fibrillar aggregates. These aggregates can act as templates to catalyze the conformational conversion of newly synthesized CPEB3, forming self-perpetuating active complexes that specifically bind to the postsynaptic density. This persistently activates the translation of key synaptic protein mRNAs, such as AMPA receptor subunits GluA1/GluA2. This "molecular memory" mechanism based on protein conformation converts transient synaptic activity into sustained local protein synthesis lasting days or longer, thereby stabilizing enhanced synaptic connections and providing the material basis for long-term potentiation and memory consolidation.

Figure source: The role of CPEB family proteins in the nervous system function in the norm and pathology

Central Nervous System Function: From Basic Regulation to Disease Association
 

The functions of the CPEB family extend to the maintenance of homeostasis throughout the central nervous system. In neuronal dendritic spines, CPEB1 strengthens synaptic signaling directly and provides energy for it by activating the translation of mRNAs for synaptic proteins (e.g., GluA2) and mitochondrial complex I subunits, respectively, thereby maintaining synaptic plasticity. However, CPEB dysfunction is closely associated with various nervous system diseases. For instance, during gliomagenesis, CPEB1 expression is significantly downregulated, leading to the loss of its translational activation of the cell cycle inhibitor protein p27^Kip1^ mRNA. The reduction in p27^Kip1 protein allows tumor cells to overcome cell cycle arrest, driving their abnormal proliferation and tumor progression.
 

Figure source: The role of CPEB family proteins in the nervous system function in the norm and pathology

Mouse Models
 

CPEB1 KO Mice:​ The most significant phenotype is reproductive defects, especially complete infertility in male mice, with spermatogenesis arrested at the round spermatid stage. Neurologically, the mice exhibit impaired synaptic plasticity and learning and memory abilities. Additionally, in glioma models, CPEB1 loss-of-function promotes tumor cell proliferation.
 

CPEB3 KO Mice:​ The most prominent phenotype is specific long-term memory deficits. Mice exhibit severely impaired hippocampal-dependent memory, while their short-term memory, motor coordination, and basal synaptic transmission remain normal.
 

Neuron-Specific CPEB1 Knockout Mice:​ Following neuron-specific knockout of CPEB1, mice show impairments in spatial memory and contextual fear memory tasks. Used specifically to study the physiological functions of CPEB1 in learning, memory, and synaptic plasticity, and also for constructing and studying the pathogenesis of nervous system tumors (e.g., glioma).
 

Neuron-Specific CPEB3 Knockout Mice:​ A key tool for studying the mechanisms of long-term memory consolidation, exhibiting severe long-term memory deficits in hippocampal-dependent memory tasks (e.g., object location memory, contextual fear memory).
 

CPEB2-hnRNPA1PrDs Humanized Mice:​ Specifically exhibit phenotypes such as muscle weakness, impaired motor coordination, or memory deficits. Used to reveal how the prion-like domains of different RNA-binding proteins cross-interact in neurodegenerative diseases (e.g., Amyotrophic Lateral Sclerosis, ALS), collectively driving abnormal protein aggregation and neuronal toxicity.
 

References:

1.Huang YS, Mendez R, Fernandez M, Richter JD. CPEB and translational control by cytoplasmic polyadenylation: impact on synaptic plasticity, learning, and memory. Mol Psychiatry. 2023 Jul;28(7):2728-2736. doi: 10.1038/s41380-023-02088-x. Epub 2023 May 2. PMID: 37131078; PMCID: PMC10620108.

2.Kozlov E, Shidlovskii YV, Gilmutdinov R, Schedl P, Zhukova M. The role of CPEB family proteins in the nervous system function in the norm and pathology. Cell Biosci. 2021 Mar 31;11(1):64. doi: 10.1186/s13578-021-00577-6. PMID: 33789753; PMCID: PMC8011179.