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Gadd45? modulates aversive learning through post-transcriptional regulation of memory-related mRNAs

ABSTRACT: Learning is essential for survival, and is controlled by complex molecular mechanisms including regulation of newly synthesized mRNAs that are required to modify synaptic functions. Despite of the well-known role of RNA-binding proteins (RBPs) in mRNA functionality, their detailed regulation during memory consolidation is poorly understood. This study focuses on the brain function of the RBP Gadd45? (Growth arrest and DNA damage-inducible protein 45 alpha, encoded by the Gadd45a gene). Here, we find that hippocampal memory and long-term potentiation are strongly impaired in Gadd45a-deficient mice, a phenotype accompanied by reduced levels of memory-related mRNAs. The majority of the Gadd45?-regulated transcripts show unusually long 3´ untranslated regions (3´UTRs) that are destabilized in Gadd45a-deficient mice via a transcription-independent mechanism, leading to reduced levels of the corresponding proteins in synaptosomes. Moreover, Gadd45? can bind specifically to these memory-related mRNAs. Our study reveals a new function for extended 3´UTRs in memory consolidation and identifies Gadd45? as a novel regulator of mRNA stability.

SUBMITTER: Dr. Alejandro Aparisi Rey

PROVIDER: S-SCDT-EMBOR-2018-46022-T | biostudies-other |

REPOSITORIES: biostudies-other

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Gadd45α modulates aversive learning through post-transcriptional regulation of memory-related mRNAs.

Project description:Learning is essential for survival and is controlled by complex molecular mechanisms including regulation of newly synthesized mRNAs that are required to modify synaptic functions. Despite the well-known role of RNA-binding proteins (RBPs) in mRNA functionality, their detailed regulation during memory consolidation is poorly understood. This study focuses on the brain function of the RBP Gadd45α (growth arrest and DNA damage-inducible protein 45 alpha, encoded by the Gadd45a gene). Here, we find that hippocampal memory and long-term potentiation are strongly impaired in Gadd45a-deficient mice, a phenotype accompanied by reduced levels of memory-related mRNAs. The majority of the Gadd45α-regulated transcripts show unusually long 3' untranslated regions (3'UTRs) that are destabilized in Gadd45a-deficient mice via a transcription-independent mechanism, leading to reduced levels of the corresponding proteins in synaptosomes. Moreover, Gadd45α can bind specifically to these memory-related mRNAs. Our study reveals a new function for extended 3'UTRs in memory consolidation and identifies Gadd45α as a novel regulator of mRNA stability.

| S-EPMC6549022 | biostudies-literature

Gadd45a modulates aversive learning through post-transcriptional regulation of memory-related mRNAs

Project description:Learning is essential for survival, and is controlled by complex molecular mechanisms including regulation of newly synthesized mRNAs that are required to modify synaptic functions. Despite of the well-known role of RNA-binding proteins (RBPs) in mRNA functionality, their detailed regulation during memory consolidation is poorly understood. This study focuses on the brain function of the RBP Gadd45α (Growth arrest and DNA damage-inducible protein 45 alpha, encoded by the Gadd45a gene). Here, we find that hippocampal memory and long-term potentiation are strongly impaired in Gadd45a-deficient mice, a phenotype accompanied by reduced levels of memory-related mRNAs. The majority of the Gadd45α-regulated transcripts show unusually long 3´ untranslated regions (3´UTRs) that are destabilized in Gadd45a-deficient mice via a transcription-independent mechanism, leading to reduced levels of the corresponding proteins in synaptosomes. Moreover, Gadd45α can bind specifically to these memory-related mRNAs. Our study reveals a new function for extended 3´UTRs in memory consolidation and identifies Gadd45α as a novel regulator of mRNA stability.

2019-04-01 | GSE100923 | GEO

Aversive learning modulates cortical representations of object categories.

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Ksp1-dependent phosphorylation of eIF4G modulates post-transcriptional regulation of specific mRNAs under glucose deprivation conditions.

Project description:Post-transcriptional regulation is an important mechanism for modulating gene expression and is performed by numerous mRNA-binding proteins. To understand the mechanisms underlying post-transcriptional regulation, we investigated the phosphorylation status of 32 mRNA-binding proteins under glucose deprivation conditions in Saccharomyces cerevisiae. We identified 17 glucose-sensitive phosphoproteins and signal pathways implicated in their phosphorylation. Notably, phosphorylation of the eukaryotic translation initiation factor 4G (eIF4G) was regulated by both the Snf1/AMPK pathway and the target of rapamycin complex 1 (TORC1) pathway. The serine/threonine protein kinase Ksp1 has previously been suggested to be a downstream effector of TORC1, but its detailed function has rarely been discussed. We identified that Snf1/AMPK and TORC1 signalings converge on Ksp1, which phosphorylates eIF4G under glucose deprivation conditions. Ksp1-dependent phosphorylation of eIF4G regulates the degradation of specific mRNAs (e.g. glycolytic mRNAs and ribosomal protein mRNAs) under glucose deprivation conditions likely through the recruitment of Dhh1. Taken together, our results suggest that Ksp1 functions as a novel modulator of post-transcriptional regulation in yeast.

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Myoinhibitory peptide signaling modulates aversive gustatory learning in Caenorhabditis elegans.

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Aversive learning strengthens episodic memory in both adolescents and adults.

Project description:Adolescence is often filled with positive and negative emotional experiences that may change how individuals remember and respond to stimuli in their environment. In adults, aversive events can both enhance memory for associated stimuli as well as generalize to enhance memory for unreinforced but conceptually related stimuli. The present study tested whether learned aversive associations similarly lead to better memory and generalization across a category of stimuli in adolescents. Participants completed an olfactory Pavlovian category conditioning task in which trial-unique exemplars from one of two categories were partially reinforced with an aversive odor. Participants then returned 24 h later to complete a recognition memory test. We found better corrected recognition memory for the reinforced versus the unreinforced category of stimuli in both adults and adolescents. Further analysis revealed that enhanced recognition memory was driven specifically by better memory for the reinforced exemplars. Autonomic arousal during learning was also related to subsequent memory. These findings build on previous work in adolescent and adult humans and rodents showing comparable acquisition of aversive Pavlovian conditioned responses across age groups and demonstrate that memory for stimuli with an acquired aversive association is enhanced in both adults and adolescents.

| S-EPMC6581005 | biostudies-literature

Genetic Dissection of Aversive Associative Olfactory Learning and Memory in Drosophila Larvae.

Project description:Memory formation is a highly complex and dynamic process. It consists of different phases, which depend on various neuronal and molecular mechanisms. In adult Drosophila it was shown that memory formation after aversive Pavlovian conditioning includes-besides other forms-a labile short-term component that consolidates within hours to a longer-lasting memory. Accordingly, memory formation requires the timely controlled action of different neuronal circuits, neurotransmitters, neuromodulators and molecules that were initially identified by classical forward genetic approaches. Compared to adult Drosophila, memory formation was only sporadically analyzed at its larval stage. Here we deconstruct the larval mnemonic organization after aversive olfactory conditioning. We show that after odor-high salt conditioning larvae form two parallel memory phases; a short lasting component that depends on cyclic adenosine 3'5'-monophosphate (cAMP) signaling and synapsin gene function. In addition, we show for the first time for Drosophila larvae an anesthesia resistant component, which relies on radish and bruchpilot gene function, protein kinase C activity, requires presynaptic output of mushroom body Kenyon cells and dopamine function. Given the numerical simplicity of the larval nervous system this work offers a unique prospect for studying memory formation of defined specifications, at full-brain scope with single-cell, and single-synapse resolution.

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dGLYAT modulates Gadd45-mediated JNK activation and cell invasion.

Project description:BackgroundCell invasion is a crucial step of tumor metastasis, finding new regulators of which offers potential drug targets for cancer therapy. Aberrant GLYAT expression is associated with human cancers, yet its role in cancer remains unknown. This study aims to understand the function and mechanism of Drosophila GLYAT in cell invasion.ResultsWe found that dGLYAT regulates Gadd45-mediated JNK pathway activation and cell invasion. Firstly, loss of dGLYAT suppressed scrib depletion- or Egr overexpression-induced JNK pathway activation and invasive cell migration. Secondary, mRNA-seq analysis identified Gadd45 as a potential transcriptional target of dGLYAT, as depletion of dGLYAT decreased Gadd45 mRNA level. Finally, Gadd45 knockdown suppressed scrib depletion-induced JNK pathway activation and cell invasion.ConclusionsThese evidences reveal the role of dGLYAT and Gadd45 in JNK-dependent cell invasion, and provide insight for the roles of their human homologs in cancers.

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