Neuronal activity regulates the nuclear proteome to promote activity-dependent transcription

Herbst, Wendy A.; Deng, Weixian; Wohlschlegel, James A.; Achiro, Jennifer M.; Martin, Kelsey C.

doi:10.1083/jcb.202103087

Cited by 6 publications

(9 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because neuronal proteastasis is expected to differ between cellular compartments, our studies could not capture spatially resolved effects of activity on proteasomal control. The regulation of proteastasis in the context of activity state, mechanisms of degradation, and subcellular location of action remain poorly understood ( Tai et al, 2010 ; Herbst et al, 2021 ; Soykan et al, 2021 ; Türker et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins

et al. 2022

View full text Add to dashboard Cite

Neuronal activity initiates signaling cascades that culminate in diverse outcomes including structural and functional neuronal plasticity, and metabolic changes. While studies have revealed activity-dependent neuronal cell type-specific transcriptional changes, unbiased quantitative analysis of cell-specific activity-induced dynamics in newly synthesized proteins (NSPs) synthesis in vivo has been complicated by cellular heterogeneity and a relatively low abundance of NSPs within the proteome in the brain. Here we combined targeted expression of mutant MetRS (methionine tRNA synthetase) in genetically defined cortical glutamatergic neurons with tight temporal control of treatment with the noncanonical amino acid, azidonorleucine, to biotinylate NSPs within a short period after pharmacologically induced seizure in male and female mice. By purifying peptides tagged with heavy or light biotin-alkynes and using direct tandem mass spectrometry detection of biotinylated peptides, we quantified activity-induced changes in cortical glutamatergic neuron NSPs. Seizure triggered significant changes in ∼300 NSPs, 33% of which were decreased by seizure. Proteins mediating excitatory and inhibitory synaptic plasticity, including SynGAP1, Pak3, GEPH1, Copine-6, and collybistin, and DNA and chromatin remodeling proteins, including Rad21, Smarca2, and Ddb1, are differentially synthesized in response to activity. Proteins likely to play homeostatic roles in response to activity, such as regulators of proteastasis, intracellular ion control, and cytoskeleton remodeling proteins, are activity induced. Conversely, seizure decreased newly synthetized NCAM, among others, suggesting that seizure induced degradation. Overall, we identified quantitative changes in the activity-induced nascent proteome from genetically defined cortical glutamatergic neurons as a strategy to discover downstream mediators of neuronal plasticity and generate hypotheses regarding their function. SIGNIFICANCE STATEMENT Activity-induced neuronal and synaptic plasticity are mediated by changes in the protein landscape, including changes in the activity-induced newly synthesized proteins; however, identifying neuronal cell type-specific nascent proteome dynamics in the intact brain has been technically challenging. We conducted an unbiased proteomic screen from which we identified significant activity-induced changes in ∼300 newly synthesized proteins in genetically defined cortical glutamatergic neurons within 20 h after pharmacologically induced seizure. Bioinformatic analysis of the dynamic nascent proteome indicates that the newly synthesized proteins play diverse roles in excitatory and inhibitory synaptic plasticity, chromatin remodeling, homeostatic mechanisms, and proteasomal and metabolic functions, extending our understanding of the diversity of plasticity mechanisms.

show abstract

Section: Discussionmentioning

confidence: 99%

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins

et al. 2022

View full text Add to dashboard Cite

show abstract

“…In following up on one of the candidate proteins, Programmed Cell Death Protein 4 (PDCD40), whose nuclear concentration was decreased by glutamatergic stimulation, Wendy identified a novel mechanism for altering the subcellular concentration of PDCD4. This involved stimulus-induced, PKC-mediated nuclear proteolysis of PDCD4 (Herbst et al, 2021). While PDCD4 has been shown to function as a translational regulator in cancer cells, Wendy's findings also supported a role for PDCD4 in transcriptional regulation, and using RNA-sequencing, suggested a specific role in transcription of genes encoding synaptic proteins.…”

Section: Postdoctoral Trainingmentioning

confidence: 93%

Kelsey Catherine Martin

2022

The History of Neuroscience in Autobiography, Volume 12

View full text Add to dashboard Cite

Martin's research focuses on the cell and molecular biology of long-term synaptic plasticity and memory, asking specifically how experience alters gene expression within neurons to change neuronal connectivity in the brain. She demonstrated that long-lasting, transcription-dependent plasticity can occur at specific synapses made by a single neuron and went on to elucidate a role for mRNA localization and local translation during synapse-specific forms of plasticity. Together, her studies have revealed the importance of both transcriptionaland post-transcriptional mechanisms of gene regulation during long-term plasticity and memory. Her laboratory identified pathways and molecules that travel from stimulated synapses to the nucleus to impact transcription, and mechanisms and molecules that regulate the localization, stability and translation of mRNAs at synapses during synapse formation and long-term synaptic plasticity. In addition to her research, she has been dedicated to advancing biomedical research and academic medicine, including serving as dean of the

show abstract

“…Vast evidence shows that miRNA expression patterns are regulated by neuronal activity 68,69,71,73,123,130–137 …”

Section: Activity‐dependent Regulation Of Mirna Expressionmentioning

confidence: 99%

“…Neuronal activity regulates protein synthesis both from preexisting mRNAs and by inducing de novo expression of genes 157,158 . The evidence of the role of neuronal activity in the regulation of gene expression and shaping the transcriptome in neurons is overwhelming 54,136,159–171 …”

Section: Neural Regulation Of Gene Expressionmentioning

confidence: 99%

“…Adequate evidence shows that, in response to external and internal stimuli, neuronal activity induces the expression of specific genes not only in neurons, but also in non‐neuronal cells, such as astrocytes, 171,177–180 muscle cells, 136,181–184 prostate, 185,186 pancreas, 187,188 adrenal gland, 189,190 liver, 191 and anterior pituitary (adenohypophysis) cells 192 …”

Section: Neural Regulation Of Gene Expressionmentioning

confidence: 99%

See 1 more Smart Citation

On the origin and nature of nongenetic information in eumetazoans

Cabej

2023

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

Nongenetic information implies all the forms of biological information not related to genes and DNA in general. Despite the deep scientific relevance of the concept, we currently lack reliable knowledge about its carriers and origins; hence, we still do not understand its true nature. Given that genes are the targets of nongenetic information, it appears that a parsimonious approach to find the ultimate source of that information is to trace back the sequential steps of the causal chain upstream of the target genes up to the ultimate link as the source of the nongenetic information. From this perspective, I examine seven nongenetically determined phenomena: placement of locus‐specific epigenetic marks on DNA and histones, changes in snRNA expression patterns, neural induction of gene expression, site‐specific alternative gene splicing, predator‐induced morphological changes, and cultural inheritance. Based on the available evidence, I propose a general model of the common neural origin of all these forms of nongenetic information in eumetazoans.

show abstract

Neuronal activity regulates the nuclear proteome to promote activity-dependent transcription

Cited by 6 publications

References 88 publications

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins

Kelsey Catherine Martin

On the origin and nature of nongenetic information in eumetazoans

Contact Info

Product

Resources

About