Attila Stetak - Academia.edu (original) (raw)
Papers by Attila Stetak
Molecular Neurobiology, Nov 15, 2022
Musashi RNA-binding proteins (MSIs) retain a pivotal role in stem cell maintenance, tumorigenesis... more Musashi RNA-binding proteins (MSIs) retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, we showed in C. elegans that Musashi (MSI-1) actively promotes forgetting upon associative learning via a 3'UTR-dependent translational expression of the Arp2/3 actin branching complex. Here, we investigated the evolutionary conserved role of MSI proteins and the effect of their pharmacological inhibition on memory. Expression of human Musashi 1 (MSI1) and Musashi 2 (MSI2) under the endogenous Musashi promoter fully rescued the phenotype of msi-1(lf) worms. Furthermore, pharmacological inhibition of human MSI1 and MSI2 activity using (-)-gossypol resulted in improved memory retention, without causing locomotor, chemotactic, or learning deficits. No drug effect was observed in msi-1(lf) treated worms. Using Western blotting and confocal microscopy, we found no changes in MSI-1 protein abundance following (-)-gossypol treatment, suggesting that Musashi gene expression remains unaltered and that the compound exerts its inhibitory effect post-translationally. Additionally, (-)-gossypol suppressed the previously seen rescue of the msi-1(lf) phenotype in worms expressing human MSI1 specifically in the AVA neuron, indicating that (-)-gossypol can regulate the Musashi pathway in a memory-related neuronal circuit in worms. Finally, treating aged worms with (-)-gossypol reversed physiological age-dependent memory decline. Taken together, our findings indicate that pharmacological inhibition of Musashi might represent a promising approach for memory modulation.
SUMMARYThe AMPA subtype of ionotropic glutamate receptors (AMPARs) plays an essential role in exc... more SUMMARYThe AMPA subtype of ionotropic glutamate receptors (AMPARs) plays an essential role in excitatory synaptic transmission, learning, and memory. The majority of AMPARs are made in the cell body and are transported by molecular motors to synapses. Maintaining the proper number of synaptic receptors requires coordinated regulation of receptor production, export from the soma and delivery at synapses. This major logistical process is essential for circuit function and behavior. Although recent studies have shown that long-distance synaptic transport is regulated by neuronal activity, little is known about the mechanisms that coordinate somatic export or synaptic delivery and removal. Here we show that loss of the PTP-3A isoform of the receptor tyrosine phosphatase PTP-3 (the C. elegans homologue of vertebrate LAR-RPTP) leads to a ∼60% decrease in AMPAR transport; this affects synaptic delivery of AMPARs and synaptic functions necessary for long-term associative olfactory memory in...
PLOS Genetics
The Musashi family of RNA-binding proteins controls several biological processes including stem c... more The Musashi family of RNA-binding proteins controls several biological processes including stem cell maintenance, cell division and neural function. Previously, we demonstrated that the C. elegans Musashi ortholog, msi-1, regulates forgetting via translational repression of the Arp2/3 actin-branching complex. However, the mechanisms controlling MSI-1 activity during the regulation of forgetting are currently unknown. Here we investigated the effects of protein phosphorylation on MSI-1 activity. We showed that MSI-1 function is likely controlled by alterations of its activity rather than its expression levels. Furthermore, we found that MSI-1 is phosphorylated and using mass spectrometry we identified MSI-1 phosphorylation at three residues (T18, S19 and S34). CRISPR-based manipulations of MSI-1 phosphorylation sites revealed that phosphorylation is necessary for MSI-1 function in both short- and long-term aversive olfactory associative memory. Thus, our study provides insight into t...
European Neuropsychopharmacology
Strong memory of a traumatic event is thought to contribute to the development and symptoms of po... more Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder.
Y-box-binding proteins reveals tissue-specific functions and a critical role in the formation of ... more Y-box-binding proteins reveals tissue-specific functions and a critical role in the formation of polysomes
Current Biology, 2021
Highlights d MPS-2/KCNE controls long-term associative memory d MPS-2 is in complex and acts thro... more Highlights d MPS-2/KCNE controls long-term associative memory d MPS-2 is in complex and acts through KVS-3 and KVS-4 voltage-gated K + channels d Age-dependent memory decline is linked to MPS-2 expression levels d NHR-66 actively represses MPS-2 expression, controlling age-dependent memory decline
European Neuropsychopharmacology, 2019
the deletion boundaries and strengthened between the deletion proximal regions. We detected a cha... more the deletion boundaries and strengthened between the deletion proximal regions. We detected a change in the manner in which chromosome 22q folds onto itself, namely by increasing the long-range contacts between the telomeric end and the deletion proximal region. Further, the large CNV affects the topological domain that is spanning its genomic region. Finally, there is a widespread and complex effect on chromosome interactions genome-wide, i.e. involving all other autosomes, with some of the effect directly tied to the deletion region on 22q11.2. Discussion: These findings outline novel principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity. Our work demonstrates that there are molecular mechanisms other than the gene expression changes that result from the alteration of the copy number of a given gene, that should be taken into account when studying this problem. Multiple molecular levels of control should be assayed and analyzed in an integrated fashion when studying this essential phenomenon of human genome biology and pathophysiology.
Journal of Psychiatric Research, 2016
DNA methylation represents an important link between structural genetic variation and complex phe... more DNA methylation represents an important link between structural genetic variation and complex phenotypes. The study of genome-wide CpG methylation and its relation to traits relevant to psychiatry has become increasingly important. Here, we analyzed quality metrics of 394,043 CpG sites in two samples of 568 and 319 mentally healthy young adults. For 25% of all CpGs we observed medium to large common epigenetic variation. These CpGs were overrepresented in open sea and shore regions, as well as in intergenic regions. They also showed a strong enrichment of significant hits in association analyses. Furthermore, a significant proportion of common DNA methylation is at least partially genetically driven and thus may be observed similarly across tissues. These findings could be of particular relevance for studies of complex neuropsychiatric traits, which often rely on proxy tissues.
The Embo Journal, Feb 3, 2012
Identifying molecular mechanisms that underlie learning and memory is one of the major challenges... more Identifying molecular mechanisms that underlie learning and memory is one of the major challenges in neuroscience. Taken the advantages of the nematode Caenorhabditis elegans, we investigated ?-adducin (add-1) in aversive olfactory associative learning and memory. Loss of add-1 function selectively impaired short- and long-term memory without causing acquisition, sensory, or motor deficits. We showed that ?-adducin is required for consolidation of synaptic plasticity, for sustained synaptic increase of AMPA-type glutamate receptor (GLR-1) content and altered GLR-1 turnover dynamics. ADD-1, in a splice-form- and tissue-specific manner, controlled the storage of memories presumably through actin-capping activity. In support of the C. elegans results, genetic variability of the human ADD1 gene was significantly associated with episodic memory performance in healthy young subjects. Finally, human ADD1 expression in nematodes restored loss of C. elegans add-1 gene function. Taken together, our findings support a role for ?-adducin in memory from nematodes to humans. Studying the molecular and genetic underpinnings of memory across distinct species may be helpful in the development of novel strategies to treat memory-related diseases
Proceedings of the National Academy of Sciences, 2012
Strong memory of a traumatic event is thought to contribute to the development and symptoms of po... more Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα ( PRKCA ) was associated with memory capacity—including aversive memory—in nontraumatized subjects of European descent. This finding was replicated in an independent sample of nontraumatized subjects, who additionally underwent functional magnetic resonance imaging (fMRI). fMRI analysis revealed PRKCA genotype-dependent brain activation differences during successful encoding of aversive information. Further, the identified genetic variant was also related to traumatic memory and to the risk for PTSD in heavily traumatized survivors of the Rwandan genocide. Our results indicate a role for PKCα in memory and suggest a genetic link between memory and the risk for PTSD.
Cancer Research, 2007
Cancer cells often fail to respond to stimuli that normally activate their intrinsic apoptotic ma... more Cancer cells often fail to respond to stimuli that normally activate their intrinsic apoptotic machinery. Moreover, they are able to adapt to hypoxia by changing their glycolytic rate. Pyruvate kinase (PK) is a rate-limiting enzyme in glycolysis that is converted to a less active dimer form of PKM2 isoenzyme during oncogenesis. Here, we show that both somatostatin and the structural analogue TT-232 interact with the PKM subtype. We further show that the PKM2 is translocated to the nucleus in response to TT-232 and different apoptotic agents. Nuclear translocation of PKM2 is sufficient to induce cell death that is caspase independent, isoform specific, and independent of its enzymatic activity. These results show that the tumor marker PKM2 plays a general role in caspase-independent cell death of tumor cells and thereby defines this glycolytic enzyme as a novel target for cancer therapy development. [Cancer Res 2007;67(4):1602–8]
Musashi RNA-binding proteins retain a pivotal role in stem cell maintenance, tumorigenesis, and n... more Musashi RNA-binding proteins retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, we showed in C. elegans that MSI1 actively promotes forgetting upon associative learning via modulation of cytoskeletal changes in the synapse. Here, we investigated the evolutionary conserved role of MSI proteins and the effect of their pharmacological inhibition on memory. Expression of human MSI1 and MSI2 under the endogenous musashi promoter fully rescued the phenotype of msi-1(lf) worms. Furthermore, pharmacological inhibition of MSI1 and MSI2 activity using (-)- gossypol resulted in improved memory retention, without causing locomotor, chemotactic or learning deficits. No drug effect was observed in msi-1(lf) treated worms. Using Western blotting and confocal microscopy we found no changes in MSI-1 protein abundance following (-)- gossypol treatment, suggesting that musashi gene expression remains unaltered and that the compound exerts its inhib...
European Neuropsychopharmacology
Translational Psychiatry
The neural cell adhesion molecule 1 (NCAM-1) has been implicated in several brain-related biologi... more The neural cell adhesion molecule 1 (NCAM-1) has been implicated in several brain-related biological processes, including neuronal migration, axonal branching, fasciculation, and synaptogenesis, with a pivotal role in synaptic plasticity. Here, we investigated the evolutionary conserved role of NCAM-1 in learning and memory. First, we investigated sustained changes in ncam-1 expression following aversive olfactory conditioning in C. elegans using molecular genetic methods. Furthermore, we examined the link between epigenetic signatures of the NCAM1 gene and memory in two human samples of healthy individuals (N = 568 and N = 319) and in two samples of traumatized individuals (N = 350 and N = 463). We found that olfactory conditioning in C. elegans induced ncam-1 expression and that loss of ncam-1 function selectively impaired associative long-term memory, without causing acquisition, sensory, or short-term memory deficits. Reintroduction of the C. elegans or human NCAM1 fully rescued...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 7, 2017
The identification of genes related to encoding, storage, and retrieval of memories is a major in... more The identification of genes related to encoding, storage, and retrieval of memories is a major interest in neuroscience. In the current study, we analyzed the temporal gene expression changes in a neuronal mRNA pool during an olfactory long-term associative memory (LTAM) in C. elegans hermaphrodites. Here we identified a core set of 712 (538 upregulated and 174 downregulated) genes that follow three distinct temporal peaks demonstrating multiple gene regulation waves in LTAM. Comparing with the previously published positive LTAM gene sets (Lakhina et al., 2015), 50% of the identified upregulated genes here overlap with the previous dataset, possibly representing stimulus-independent memory regulated genes. On the other hand, the remaining genes were previously not identified in positive associative memory, and may specifically regulate aversive LTAM. Our results suggest a multistep gene activation process during the formation and retrieval of long-term memory and define general memo...
Cell, 2014
A plastic nervous system requires the ability not only to acquire and store but also to forget. H... more A plastic nervous system requires the ability not only to acquire and store but also to forget. Here, we report that musashi (msi-1) is necessary for timedependent memory loss in C. elegans. Tissuespecific rescue demonstrates that MSI-1 function is necessary in the AVA interneuron. Using RNA-binding protein immunoprecipitation (IP), we found that MSI-1 binds to mRNAs of three subunits of the Arp2/3 actin branching regulator complex in vivo and downregulates ARX-1, ARX-2, and ARX-3 translation upon associative learning. The role of msi-1 in forgetting is also reflected by the persistence of learning-induced GLR-1 synaptic size increase in msi-1 mutants. We demonstrate that memory length is regulated cooperatively through the activation of adducin (add-1) and by the inhibitory effect of msi-1. Thus, a GLR-1/MSI-1/Arp2/3 pathway induces forgetting and represents a novel mechanism of memory decay by linking translational control to the structure of the actin cytoskeleton in neurons.
Nucleic acids research, 2014
The cold shock domain is one of the most highly conserved motifs between bacteria and higher euka... more The cold shock domain is one of the most highly conserved motifs between bacteria and higher eukaryotes. Y-box-binding proteins represent a subfamily of cold shock domain proteins with pleiotropic functions, ranging from transcription in the nucleus to translation in the cytoplasm. These proteins have been investigated in all major model organisms except Caenorhabditis elegans. In this study, we set out to fill this gap and present a functional characterization of CEYs, the C. elegans Y-box-binding proteins. We find that, similar to other organisms, CEYs are essential for proper gametogenesis. However, we also report a novel function of these proteins in the formation of large polysomes in the soma. In the absence of the somatic CEYs, polysomes are dramatically reduced with a simultaneous increase in monosomes and disomes, which, unexpectedly, has no obvious impact on animal biology. Because transcripts that are enriched in polysomes in wild-type animals tend to be less abundant in ...
Biochem Biophys Res Commun, 2001
While the early transient activation of Erk/MAPK was found to be important for the induction of c... more While the early transient activation of Erk/MAPK was found to be important for the induction of cell cycle arrest, the signaling pathway leading to the activation of Erk/MAPK had not been fully established. Here we present evidence that activation of the Erk/MAPK pathway by TT-232 involves PI 3-kinase, PKC␦ and the protein tyrosine phosphatase ␣ (PTP␣). We show a physical interaction of PI 3-kinase and PKC␦ with PTP␣ and show that the tyrosine phosphatase plays a role in the activation of MAPK. In this process, PTP␣ Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60 c-src . Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKC␦ and PTP␣ in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232.
Molecular Neurobiology, Nov 15, 2022
Musashi RNA-binding proteins (MSIs) retain a pivotal role in stem cell maintenance, tumorigenesis... more Musashi RNA-binding proteins (MSIs) retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, we showed in C. elegans that Musashi (MSI-1) actively promotes forgetting upon associative learning via a 3'UTR-dependent translational expression of the Arp2/3 actin branching complex. Here, we investigated the evolutionary conserved role of MSI proteins and the effect of their pharmacological inhibition on memory. Expression of human Musashi 1 (MSI1) and Musashi 2 (MSI2) under the endogenous Musashi promoter fully rescued the phenotype of msi-1(lf) worms. Furthermore, pharmacological inhibition of human MSI1 and MSI2 activity using (-)-gossypol resulted in improved memory retention, without causing locomotor, chemotactic, or learning deficits. No drug effect was observed in msi-1(lf) treated worms. Using Western blotting and confocal microscopy, we found no changes in MSI-1 protein abundance following (-)-gossypol treatment, suggesting that Musashi gene expression remains unaltered and that the compound exerts its inhibitory effect post-translationally. Additionally, (-)-gossypol suppressed the previously seen rescue of the msi-1(lf) phenotype in worms expressing human MSI1 specifically in the AVA neuron, indicating that (-)-gossypol can regulate the Musashi pathway in a memory-related neuronal circuit in worms. Finally, treating aged worms with (-)-gossypol reversed physiological age-dependent memory decline. Taken together, our findings indicate that pharmacological inhibition of Musashi might represent a promising approach for memory modulation.
SUMMARYThe AMPA subtype of ionotropic glutamate receptors (AMPARs) plays an essential role in exc... more SUMMARYThe AMPA subtype of ionotropic glutamate receptors (AMPARs) plays an essential role in excitatory synaptic transmission, learning, and memory. The majority of AMPARs are made in the cell body and are transported by molecular motors to synapses. Maintaining the proper number of synaptic receptors requires coordinated regulation of receptor production, export from the soma and delivery at synapses. This major logistical process is essential for circuit function and behavior. Although recent studies have shown that long-distance synaptic transport is regulated by neuronal activity, little is known about the mechanisms that coordinate somatic export or synaptic delivery and removal. Here we show that loss of the PTP-3A isoform of the receptor tyrosine phosphatase PTP-3 (the C. elegans homologue of vertebrate LAR-RPTP) leads to a ∼60% decrease in AMPAR transport; this affects synaptic delivery of AMPARs and synaptic functions necessary for long-term associative olfactory memory in...
PLOS Genetics
The Musashi family of RNA-binding proteins controls several biological processes including stem c... more The Musashi family of RNA-binding proteins controls several biological processes including stem cell maintenance, cell division and neural function. Previously, we demonstrated that the C. elegans Musashi ortholog, msi-1, regulates forgetting via translational repression of the Arp2/3 actin-branching complex. However, the mechanisms controlling MSI-1 activity during the regulation of forgetting are currently unknown. Here we investigated the effects of protein phosphorylation on MSI-1 activity. We showed that MSI-1 function is likely controlled by alterations of its activity rather than its expression levels. Furthermore, we found that MSI-1 is phosphorylated and using mass spectrometry we identified MSI-1 phosphorylation at three residues (T18, S19 and S34). CRISPR-based manipulations of MSI-1 phosphorylation sites revealed that phosphorylation is necessary for MSI-1 function in both short- and long-term aversive olfactory associative memory. Thus, our study provides insight into t...
European Neuropsychopharmacology
Strong memory of a traumatic event is thought to contribute to the development and symptoms of po... more Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder.
Y-box-binding proteins reveals tissue-specific functions and a critical role in the formation of ... more Y-box-binding proteins reveals tissue-specific functions and a critical role in the formation of polysomes
Current Biology, 2021
Highlights d MPS-2/KCNE controls long-term associative memory d MPS-2 is in complex and acts thro... more Highlights d MPS-2/KCNE controls long-term associative memory d MPS-2 is in complex and acts through KVS-3 and KVS-4 voltage-gated K + channels d Age-dependent memory decline is linked to MPS-2 expression levels d NHR-66 actively represses MPS-2 expression, controlling age-dependent memory decline
European Neuropsychopharmacology, 2019
the deletion boundaries and strengthened between the deletion proximal regions. We detected a cha... more the deletion boundaries and strengthened between the deletion proximal regions. We detected a change in the manner in which chromosome 22q folds onto itself, namely by increasing the long-range contacts between the telomeric end and the deletion proximal region. Further, the large CNV affects the topological domain that is spanning its genomic region. Finally, there is a widespread and complex effect on chromosome interactions genome-wide, i.e. involving all other autosomes, with some of the effect directly tied to the deletion region on 22q11.2. Discussion: These findings outline novel principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity. Our work demonstrates that there are molecular mechanisms other than the gene expression changes that result from the alteration of the copy number of a given gene, that should be taken into account when studying this problem. Multiple molecular levels of control should be assayed and analyzed in an integrated fashion when studying this essential phenomenon of human genome biology and pathophysiology.
Journal of Psychiatric Research, 2016
DNA methylation represents an important link between structural genetic variation and complex phe... more DNA methylation represents an important link between structural genetic variation and complex phenotypes. The study of genome-wide CpG methylation and its relation to traits relevant to psychiatry has become increasingly important. Here, we analyzed quality metrics of 394,043 CpG sites in two samples of 568 and 319 mentally healthy young adults. For 25% of all CpGs we observed medium to large common epigenetic variation. These CpGs were overrepresented in open sea and shore regions, as well as in intergenic regions. They also showed a strong enrichment of significant hits in association analyses. Furthermore, a significant proportion of common DNA methylation is at least partially genetically driven and thus may be observed similarly across tissues. These findings could be of particular relevance for studies of complex neuropsychiatric traits, which often rely on proxy tissues.
The Embo Journal, Feb 3, 2012
Identifying molecular mechanisms that underlie learning and memory is one of the major challenges... more Identifying molecular mechanisms that underlie learning and memory is one of the major challenges in neuroscience. Taken the advantages of the nematode Caenorhabditis elegans, we investigated ?-adducin (add-1) in aversive olfactory associative learning and memory. Loss of add-1 function selectively impaired short- and long-term memory without causing acquisition, sensory, or motor deficits. We showed that ?-adducin is required for consolidation of synaptic plasticity, for sustained synaptic increase of AMPA-type glutamate receptor (GLR-1) content and altered GLR-1 turnover dynamics. ADD-1, in a splice-form- and tissue-specific manner, controlled the storage of memories presumably through actin-capping activity. In support of the C. elegans results, genetic variability of the human ADD1 gene was significantly associated with episodic memory performance in healthy young subjects. Finally, human ADD1 expression in nematodes restored loss of C. elegans add-1 gene function. Taken together, our findings support a role for ?-adducin in memory from nematodes to humans. Studying the molecular and genetic underpinnings of memory across distinct species may be helpful in the development of novel strategies to treat memory-related diseases
Proceedings of the National Academy of Sciences, 2012
Strong memory of a traumatic event is thought to contribute to the development and symptoms of po... more Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα ( PRKCA ) was associated with memory capacity—including aversive memory—in nontraumatized subjects of European descent. This finding was replicated in an independent sample of nontraumatized subjects, who additionally underwent functional magnetic resonance imaging (fMRI). fMRI analysis revealed PRKCA genotype-dependent brain activation differences during successful encoding of aversive information. Further, the identified genetic variant was also related to traumatic memory and to the risk for PTSD in heavily traumatized survivors of the Rwandan genocide. Our results indicate a role for PKCα in memory and suggest a genetic link between memory and the risk for PTSD.
Cancer Research, 2007
Cancer cells often fail to respond to stimuli that normally activate their intrinsic apoptotic ma... more Cancer cells often fail to respond to stimuli that normally activate their intrinsic apoptotic machinery. Moreover, they are able to adapt to hypoxia by changing their glycolytic rate. Pyruvate kinase (PK) is a rate-limiting enzyme in glycolysis that is converted to a less active dimer form of PKM2 isoenzyme during oncogenesis. Here, we show that both somatostatin and the structural analogue TT-232 interact with the PKM subtype. We further show that the PKM2 is translocated to the nucleus in response to TT-232 and different apoptotic agents. Nuclear translocation of PKM2 is sufficient to induce cell death that is caspase independent, isoform specific, and independent of its enzymatic activity. These results show that the tumor marker PKM2 plays a general role in caspase-independent cell death of tumor cells and thereby defines this glycolytic enzyme as a novel target for cancer therapy development. [Cancer Res 2007;67(4):1602–8]
Musashi RNA-binding proteins retain a pivotal role in stem cell maintenance, tumorigenesis, and n... more Musashi RNA-binding proteins retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, we showed in C. elegans that MSI1 actively promotes forgetting upon associative learning via modulation of cytoskeletal changes in the synapse. Here, we investigated the evolutionary conserved role of MSI proteins and the effect of their pharmacological inhibition on memory. Expression of human MSI1 and MSI2 under the endogenous musashi promoter fully rescued the phenotype of msi-1(lf) worms. Furthermore, pharmacological inhibition of MSI1 and MSI2 activity using (-)- gossypol resulted in improved memory retention, without causing locomotor, chemotactic or learning deficits. No drug effect was observed in msi-1(lf) treated worms. Using Western blotting and confocal microscopy we found no changes in MSI-1 protein abundance following (-)- gossypol treatment, suggesting that musashi gene expression remains unaltered and that the compound exerts its inhib...
European Neuropsychopharmacology
Translational Psychiatry
The neural cell adhesion molecule 1 (NCAM-1) has been implicated in several brain-related biologi... more The neural cell adhesion molecule 1 (NCAM-1) has been implicated in several brain-related biological processes, including neuronal migration, axonal branching, fasciculation, and synaptogenesis, with a pivotal role in synaptic plasticity. Here, we investigated the evolutionary conserved role of NCAM-1 in learning and memory. First, we investigated sustained changes in ncam-1 expression following aversive olfactory conditioning in C. elegans using molecular genetic methods. Furthermore, we examined the link between epigenetic signatures of the NCAM1 gene and memory in two human samples of healthy individuals (N = 568 and N = 319) and in two samples of traumatized individuals (N = 350 and N = 463). We found that olfactory conditioning in C. elegans induced ncam-1 expression and that loss of ncam-1 function selectively impaired associative long-term memory, without causing acquisition, sensory, or short-term memory deficits. Reintroduction of the C. elegans or human NCAM1 fully rescued...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 7, 2017
The identification of genes related to encoding, storage, and retrieval of memories is a major in... more The identification of genes related to encoding, storage, and retrieval of memories is a major interest in neuroscience. In the current study, we analyzed the temporal gene expression changes in a neuronal mRNA pool during an olfactory long-term associative memory (LTAM) in C. elegans hermaphrodites. Here we identified a core set of 712 (538 upregulated and 174 downregulated) genes that follow three distinct temporal peaks demonstrating multiple gene regulation waves in LTAM. Comparing with the previously published positive LTAM gene sets (Lakhina et al., 2015), 50% of the identified upregulated genes here overlap with the previous dataset, possibly representing stimulus-independent memory regulated genes. On the other hand, the remaining genes were previously not identified in positive associative memory, and may specifically regulate aversive LTAM. Our results suggest a multistep gene activation process during the formation and retrieval of long-term memory and define general memo...
Cell, 2014
A plastic nervous system requires the ability not only to acquire and store but also to forget. H... more A plastic nervous system requires the ability not only to acquire and store but also to forget. Here, we report that musashi (msi-1) is necessary for timedependent memory loss in C. elegans. Tissuespecific rescue demonstrates that MSI-1 function is necessary in the AVA interneuron. Using RNA-binding protein immunoprecipitation (IP), we found that MSI-1 binds to mRNAs of three subunits of the Arp2/3 actin branching regulator complex in vivo and downregulates ARX-1, ARX-2, and ARX-3 translation upon associative learning. The role of msi-1 in forgetting is also reflected by the persistence of learning-induced GLR-1 synaptic size increase in msi-1 mutants. We demonstrate that memory length is regulated cooperatively through the activation of adducin (add-1) and by the inhibitory effect of msi-1. Thus, a GLR-1/MSI-1/Arp2/3 pathway induces forgetting and represents a novel mechanism of memory decay by linking translational control to the structure of the actin cytoskeleton in neurons.
Nucleic acids research, 2014
The cold shock domain is one of the most highly conserved motifs between bacteria and higher euka... more The cold shock domain is one of the most highly conserved motifs between bacteria and higher eukaryotes. Y-box-binding proteins represent a subfamily of cold shock domain proteins with pleiotropic functions, ranging from transcription in the nucleus to translation in the cytoplasm. These proteins have been investigated in all major model organisms except Caenorhabditis elegans. In this study, we set out to fill this gap and present a functional characterization of CEYs, the C. elegans Y-box-binding proteins. We find that, similar to other organisms, CEYs are essential for proper gametogenesis. However, we also report a novel function of these proteins in the formation of large polysomes in the soma. In the absence of the somatic CEYs, polysomes are dramatically reduced with a simultaneous increase in monosomes and disomes, which, unexpectedly, has no obvious impact on animal biology. Because transcripts that are enriched in polysomes in wild-type animals tend to be less abundant in ...
Biochem Biophys Res Commun, 2001
While the early transient activation of Erk/MAPK was found to be important for the induction of c... more While the early transient activation of Erk/MAPK was found to be important for the induction of cell cycle arrest, the signaling pathway leading to the activation of Erk/MAPK had not been fully established. Here we present evidence that activation of the Erk/MAPK pathway by TT-232 involves PI 3-kinase, PKC␦ and the protein tyrosine phosphatase ␣ (PTP␣). We show a physical interaction of PI 3-kinase and PKC␦ with PTP␣ and show that the tyrosine phosphatase plays a role in the activation of MAPK. In this process, PTP␣ Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60 c-src . Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKC␦ and PTP␣ in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232.