Effect of depletion of atp-2 by RNA interference on gene expression during the development of Caenorhabditis elegans
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ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE241240 | GEO | 2024/03/25
REPOSITORIES: GEO
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Project description:Neuromodulatory cells transduce environmental information into long lasting behavioral responses. However, the mechanisms governing how defined neuronal cell types influence behavioral plasticity are difficult to characterize. Here we adapted the Translating Ribosome Affinity Purification (TRAP) approach in C. elegans to profile ribosome-associated mRNAs from three major tissues and the neuromodulatory dopaminergic and serotonergic cells. We identified elc-2, an Elongin C ortholog, specifically expressed in stress-sensing ADF serotonergic sensory neurons, and found that it plays a role in mediating long-lasting change in serotonin-dependent feeding behavior induced by heat stress. We demonstrate that ELC-2 and the von Hippel-Lindau protein VHL-1, components of an Elongin-Cullin-SOCS-box (ECS) E3 ubiquitin ligase, modulate this behavior after experiencing stress. Also, heat stress induces a transient redistribution of ELC-2, becoming more nuclearly enriched. Together, our results demonstrate dynamic regulation of an E3 ligase, and a role for an ECS complex in neuromodulation and control of lasting behavioral states.
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Project description:Mitochondrial functions across different tissues are regulated in a coordinated fashion to optimize fitness of the organism. Mitochondrial unfolded protein response (UPRmt) can be non-autonomously elicited by mitochondrial perturbation in neurons, but neuronal signals that propagate such response and its physiological significance remains incompletely understood. Here we show that in C. elegans, loss of neuronal fzo-1/Mitofusin induces non-autonomous UPRmt through multiple neurotransmitters and neurohormones, including acetylcholine, serotonin, glutamate, tyramine and insulin-like peptides. Neuronal fzo-1 depletion also triggers non-autonomous mitochondrial fragmentation, which requires autophagy and mitophagy genes. Systemic activation of UPRmt and mitochondrial fragmentation in C. elegans via perturbing neuronal mitochondrial dynamics improves resistance to pathogenic Pseudomonas infection, which is supported by transcriptomic signatures of immunity and stress response genes. We propose that C. elegans surveils neuronal mitochondrial dynamics that coordinate systemic UPRmt and mitochondrial connectivity for pathogen defense and optimized survival under bacterial infection.
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Project description:Auditory cued fear conditioning is a widely used behavioral paradigm to investigate associative learning and memory formation. During conditioning, an animal learns that a particular auditory stimulus predicts an aversive stimulus, a foot shock. When later confronted again with this conditional auditory stimulus rodents typically respond with a cessation of movement. The purpose of this study was to analyze the effects of auditory fear conditioning on gene expression in the auditory cortex in a number of different paradigms that control for the effect of several behavioral factors. The different paradigms were M-^SpairedM-^T were the sound and the shock are paired so that the mouse associates the tone with the noxious stimulus the shock, M-^SsoundM-^T were only the sound was presented, M-^SshockM-^T were only the shock was presented, M-^SunpairedM-^T were the sound and the shock were presented one minute apart so that the mouse cannot form an association between the sound and the shock, M-^ScontextM-^T were no sounds or shocks were presented but the mouse was in the behavior chamber and M-^SHCM-^T were the mouse was taken directly from the cage.
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Project description:Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes psychosocial stress vulnerability in mouse. This occurs through dysfunction of type 1A serotonin (5-hydroxytryptamine, 5-HT) receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knockout (D2LR-KO) male mice as compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1AR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT release in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was up-regulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1AR–activated G-protein–activated inwardly rectifying potassium (GIRK) conductance in D2LR-KO serotonergic neurons. Finally, D2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Taken together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability.
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Project description:The mitochondrial matrix is unique in that it must integrate folding and assembly of proteins derived from nuclear and mitochondrial genomes. In C. elegans, the mitochondrial unfolded protein response (UPRmt) senses matrix protein misfolding and induces a program of nuclear gene expression, including mitochondrial chaperonins, to promote mitochondrial proteostasis. While misfolded mitochondrial matrix-localized ornithine trans-carbamylase (OTC) induces chaperonin expression, our understanding of mammalian UPRmt is rudimentary, reflecting a lack of acute triggers for UPRmt activation. This limitation has prevented analysis of the cellular responses to matrix protein misfolding and the effects of UPRmt on mitochondrial translation to control protein folding loads. Here, we combine pharmacological inhibitors of matrix-localized HSP90/TRAP1 or LON protease, which promote chaperonin expression, with global transcriptional and proteomic analysis to reveal an extensive and acute response of human cells to UPRmt. This response involved widespread induction of nuclear genes, including matrix-localized proteins involved in folding, pre-RNA processing and translation. Functional studies revealed rapid but reversible translation inhibition in mitochondria occurring concurrently with defects in pre-RNA processing due to transcriptional repression and LON-dependent turnover of the mitochondrial pre-RNA processing nuclease MRPP3. This study reveals that acute mitochondrial protein folding stress activates both increased chaperone availability within the matrix and reduced matrix-localized protein synthesis through translational inhibition, and provides a framework for further dissection of mammalian UPRmt. triplicate experiment of 3 conditions (untreated, GTPP treatment, CDDO treatment)
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Project description:The mitochondrial matrix is unique in that it must integrate folding and assembly of proteins derived from nuclear and mitochondrial genomes. In C. elegans, the mitochondrial unfolded protein response (UPRmt) senses matrix protein misfolding and induces a program of nuclear gene expression, including mitochondrial chaperonins, to promote mitochondrial proteostasis. While misfolded mitochondrial matrix-localized ornithine trans-carbamylase (OTC) induces chaperonin expression, our understanding of mammalian UPRmt is rudimentary, reflecting a lack of acute triggers for UPRmt activation. This limitation has prevented analysis of the cellular responses to matrix protein misfolding and the effects of UPRmt on mitochondrial translation to control protein folding loads. Here, we combine pharmacological inhibitors of matrix-localized HSP90/TRAP1 or LON protease, which promote chaperonin expression, with global transcriptional and proteomic analysis to reveal an extensive and acute response of human cells to UPRmt. This response involved widespread induction of nuclear genes, including matrix-localized proteins involved in folding, pre-RNA processing and translation. Functional studies revealed rapid but reversible translation inhibition in mitochondria occurring concurrently with defects in pre-RNA processing due to transcriptional repression and LON-dependent turnover of the mitochondrial pre-RNA processing nuclease MRPP3. This study reveals that acute mitochondrial protein folding stress activates both increased chaperone availability within the matrix and reduced matrix-localized protein synthesis through translational inhibition, and provides a framework for further dissection of mammalian UPRmt. triplicate experiment of 2 conditions (untreated, GTPP treatment)
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