scholarly journals ELAV proteins bind and stabilize C/EBP mRNA in the induction of long-term memory in Aplysia

2020 ◽  
Author(s):  
Anastasios A. Mirisis ◽  
Ashley M. Kopec ◽  
Thomas J. Carew
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Early Gene ◽  
Long Term Memory ◽  
Term Memory ◽  
New Findings

AbstractLong-term memory (LTM) formation is a critical survival process by which an animal retains information about prior experiences in order to guide future behavior. In the experimentally advantageous marine mollusk Aplysia, LTM for sensitization can be induced by the presentation of two aversive shocks to the animal’s tail. Each of these training trials recruits distinct growth factor signaling systems that promote LTM formation. Specifically, whereas intact TrkB signaling during Trial 1 promotes an initial and transient increase of the immediate early gene apc/ebp mRNA, a prolonged increase in apc/ebp gene expression required for LTM formation requires the addition of TGFβ signaling during Trial 2. Here we explored the molecular mechanisms by which Trial 2 achieves the essential prolonged gene expression of apc/ebp. We find that this prolonged gene expression is not dependent on de novo transcription, but that apc/ebp mRNA synthesized by Trial 1 is post-transcriptionally stabilized by interacting with the RNA-binding protein ApELAV. This interaction is promoted by p38 MAPK activation initiated by TGFβ. We further demonstrate that blocking the interaction of ApELAV with its target mRNA during Trial 2 blocks both the prolonged increase in apc/ebp gene expression and the behavioral induction of LTM. Collectively, our findings elucidate both when and how ELAV proteins are recruited for the stabilization of mRNA in LTM formation.Significance StatementIn the present paper we significantly extend the general field of molecular processing in LTM by describing a novel form of pre-translational processing required for LTM which relies on the stabilization of a newly synthesized mRNA by a unique class of RNA binding proteins (ELAVs). In the broad field of molecular mechanisms of transcription-dependent LTM, there are now compelling data showing that important processing can occur after transcription of a gene, but before translation of the message into protein. Although the potential importance of ELAV proteins in LTM formation has previously been reported, to date there has been no mechanistic insight into the specific actions of ELAV proteins in stabilization of mRNAs known to be critical for LTM. Our new findings thus complement and extend this literature by demonstrating when and how this post-transcriptional gene regulation is mediated in the induction of LTM.

Genes to remember

1999 ◽  
Vol 202 (21) ◽  
pp. 2887-2891
Author(s):  
C.M. Alberini
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Camp Response Element Binding ◽  
Long Term Memory ◽  
Biological Mechanisms ◽  
Camp Response Element ◽  
Term Memory ◽  
Molecular Approaches ◽  
Complex Forms

It has been known for several decades that the formation of long-term memory requires gene expression. In recent years, the use of genetic and molecular approaches has led to the identification and characterization of genes and molecules that play a fundamental role in the biological mechanisms underlying learning and memory. From these studies, it appears that molecules and molecular mechanisms essential for the process of memory have been conserved throughout evolution. The cyclic AMP (cAMP)-dependent activation pathway and a cAMP-dependent cascade of gene expression have been shown to be essential for memory formation in Aplysia californica, Drosophila melanogaster and rodents. Moreover, members of the transcription factor family cAMP response element binding proteins (CREBs) seem to represent key molecules for transforming incoming information into long-term memory. Here, we review the studies showing that conserved molecules and biological mechanisms are engaged in simple and complex forms of memory.

scholarly journals Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

2019 ◽  
Author(s):  
David Levitan ◽  
Chenghao Liu ◽  
Tracy Yang ◽  
Yasuyuki Shima ◽  
Jian-You Lin ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Basolateral Amygdala ◽  
Molecular Mechanisms ◽  
Early Gene ◽  
Intrinsic Excitability ◽  
Long Term Memory ◽  
Projection Neurons ◽  
Term Memory ◽  
Growth Metabolism

AbstractConditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms are poorly understood, however. We used RNAseq from BLApn to identify learning-related changes in Stk11, a kinase with well-studied roles in growth, metabolism and development, but not previously implicated in learning. Deletion of Stk11 restricted to BLApn completely blocks memory when occurring prior to training, but not following it, despite altering neither BLApn-dependent encoding of taste palatability in gustatory cortex, nor transcriptional activation of BLApn during training. Deletion of Stk11 in BLApn also increases their intrinsic excitability. Conversely, BLApn activated by CTA to express the immediate early gene Fos had reduced excitability. BLApn knockout of Fos also increased excitability and impaired learning. These data suggest that Stk11 and Fos expression play key roles in CTA long-term memory formation, perhaps by modulating the intrinsic excitability of BLApn.

scholarly journals De novo proteomic methods for examining the molecular mechanisms underpinning long-term memory

2021 ◽  
Vol 169 ◽  
pp. 94-103
Author(s):  
Harrison Tudor Evans ◽  
Daniel Blackmore ◽  
Jürgen Götz ◽  
Liviu-Gabriel Bodea
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Long Term Memory ◽  
Term Memory ◽  
Proteomic Methods

scholarly journals Identification of Gene Expression Changes Associated With Long-Term Memory of Courtship Rejection in Drosophila Males

2012 ◽  
Vol 2 (11) ◽  
pp. 1437-1445 ◽  
Author(s):  
Ari Winbush ◽  
Danielle Reed ◽  
Peter L. Chang ◽  
Sergey V. Nuzhdin ◽  
Lisa C. Lyons ◽  
...  
Keyword(s):  
Gene Expression ◽  
Long Term Memory ◽  
Term Memory

The expanding world of metabolic enzymes moonlighting as RNA binding proteins

2021 ◽  
Author(s):  
Nicole J. Curtis ◽  
Constance J. Jeffery
Keyword(s):  
Gene Expression ◽  
Regulatory Networks ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Molecular Structures ◽  
Intermediary Metabolism ◽  
The Many ◽  
And Function

RNA binding proteins play key roles in many aspects of RNA metabolism and function, including splicing, transport, translation, localization, stability and degradation. Within the past few years, proteomics studies have identified dozens of enzymes in intermediary metabolism that bind to RNA. The wide occurrence and conservation of RNA binding ability across distant branches of the evolutionary tree suggest that these moonlighting enzymes are involved in connections between intermediary metabolism and gene expression that comprise far more extensive regulatory networks than previously thought. There are many outstanding questions about the molecular structures and mechanisms involved, the effects of these interactions on enzyme and RNA functions, and the factors that regulate the interactions. The effects on RNA function are likely to be wider than regulation of translation, and some enzyme–RNA interactions have been found to regulate the enzyme's catalytic activity. Several enzyme–RNA interactions have been shown to be affected by cellular factors that change under different intracellular and environmental conditions, including concentrations of substrates and cofactors. Understanding the molecular mechanisms involved in the interactions between the enzymes and RNA, the factors involved in regulation, and the effects of the enzyme–RNA interactions on both the enzyme and RNA functions will lead to a better understanding of the role of the many newly identified enzyme–RNA interactions in connecting intermediary metabolism and gene expression.

scholarly journals The CBP KIX domain regulates long-term memory and circadian activity

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Snehajyoti Chatterjee ◽  
Christopher C. Angelakos ◽  
Ethan Bahl ◽  
Joshua D. Hawk ◽  
Marie E. Gaine ◽  
...  
Keyword(s):  
Gene Expression ◽  
Morris Water Maze ◽  
Water Maze ◽  
Long Term Memory ◽  
Circadian Activity ◽  
Term Memory ◽  
Circadian Genes ◽  
Domain Protein ◽  
Kix Domain

Abstract Background CREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding protein (CBP), a multi-domain protein that binds numerous transcription factors potentially affecting expression of thousands of genes. Identifying specific domain functions for multi-domain proteins is essential to understand processes such as cognitive function and circadian clocks. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBPKIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding. Results We found that CBPKIX/KIX mice were impaired in long-term memory, but not learning acquisition or short-term memory for the Morris water maze. Using an unbiased analysis of gene expression in the dorsal hippocampus after training in the Morris water maze or contextual fear conditioning, we discovered dysregulation of CREB, CLOCK, and BMAL1 target genes and downregulation of circadian genes in CBPKIX/KIX mice. Given our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity and phase resetting in CBPKIX/KIX mice. CBPKIX/KIX mice exhibited delayed activity peaks after light offset and longer free-running periods in constant dark. Interestingly, CBPKIX/KIX mice displayed phase delays and advances in response to photic stimulation comparable to wildtype littermates. Thus, this work delineates site-specific regulation of the circadian clock by a multi-domain protein. Conclusions These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms. Graphical abstract

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