{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/299545"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/299545","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Exploring the role of the unfolded protein response in C. elegans neurons","abstract":"The nervous system of C. elegans plays a role in the orchestration of systemic stress responses. One of these stress responses, the unfolded protein response of the endoplasmic reticulum (UPRER), is activated to re-establish protein homeostasis (proteostasis) upon the detection of ER stress. Overexpression of active, spliced XBP-1 (XBP-1s), a transcription factor that acts downstream of the UPRER kinase/endoribonuclease IRE-1, in the nervous system of C. elegans increases the lifespan and healthspan of worms through UPRER induction in the intestine cell non-autonomously. To investigate XBP-1s-dependent changes in the nervous system of these animals, we conducted tissue-specific RNA-Seq in neurons. This approach allowed us to characterise differentially regulated neuronal and synaptic components, which may mediate changes to the nervous system that cause the release of inter-tissue UPRER-activating signals. Furthermore, we extended our tissue-specific RNA-Seq analyses to the intestine, using intestinal cells from neuronal xbp-1s- or intestinal xbp-1s-overexpressing worms. We identified lysosomal gene upregulation in the intestine, which leads to activation of intestinal lysosomes downstream of neuronal xbp-1s. Moreover, comparison of cell autonomous and cell non-autonomous targets of XBP-1s within the intestine showed that XBP-1s has different but overlapping sets of target genes via different activation mechanisms. We also employed a candidate screening approach based on our previous finding that neurotransmitter secretion is required for intestinal UPRER activation upon neuronal xbp-1s overexpression, and identified positive and negative regulators of intestinal UPRER activation. This showed that distal UPRER activation relies on tyramine/octopamine production, and is modulated by the worm TGF-β homologue DAF-7. We then asked whether neuronal xbp-1s can affect other systemic outputs requiring neuron-specific functions, such as the regulation of behaviour. We found that a branch of the neuronal circuitry required to activate UPRER in the intestine following neuronal XBP-1s overexpression is also required to generate neuronal xbp-1s-dependent behavioural phenotypes in food-leaving and reproduction. These findings suggest that inter-tissue UPRER activation, increased longevity and healthspan can be coordinately regulated with stress-responsive behaviour by the activation of XBP-1s in the nervous system.","abstract_html":"The nervous system of C. elegans plays a role in the orchestration of systemic stress responses. One of these stress responses, the unfolded protein response of the endoplasmic reticulum (UPRER), is activated to re-establish protein homeostasis (proteostasis) upon the detection of ER stress. Overexpression of active, spliced XBP-1 (XBP-1s), a transcription factor that acts downstream of the UPRER kinase/endoribonuclease IRE-1, in the nervous system of C. elegans increases the lifespan and healthspan of worms through UPRER induction in the intestine cell non-autonomously. To investigate XBP-1s-dependent changes in the nervous system of these animals, we conducted tissue-specific RNA-Seq in neurons. This approach allowed us to characterise differentially regulated neuronal and synaptic components, which may mediate changes to the nervous system that cause the release of inter-tissue UPRER-activating signals. Furthermore, we extended our tissue-specific RNA-Seq analyses to the intestine, using intestinal cells from neuronal xbp-1s- or intestinal xbp-1s-overexpressing worms. We identified lysosomal gene upregulation in the intestine, which leads to activation of intestinal lysosomes downstream of neuronal xbp-1s. Moreover, comparison of cell autonomous and cell non-autonomous targets of XBP-1s within the intestine showed that XBP-1s has different but overlapping sets of target genes via different activation mechanisms. We also employed a candidate screening approach based on our previous finding that neurotransmitter secretion is required for intestinal UPRER activation upon neuronal xbp-1s overexpression, and identified positive and negative regulators of intestinal UPRER activation. This showed that distal UPRER activation relies on tyramine/octopamine production, and is modulated by the worm TGF-β homologue DAF-7. We then asked whether neuronal xbp-1s can affect other systemic outputs requiring neuron-specific functions, such as the regulation of behaviour. We found that a branch of the neuronal circuitry required to activate UPRER in the intestine following neuronal XBP-1s overexpression is also required to generate neuronal xbp-1s-dependent behavioural phenotypes in food-leaving and reproduction. These findings suggest that inter-tissue UPRER activation, increased longevity and healthspan can be coordinately regulated with stress-responsive behaviour by the activation of XBP-1s in the nervous system.","abstract_has_math":false,"creators":["Ozbey, Nesem Petek"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Taylor, Rebecca"],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-12-04","date_published":"2019-12-04","updated_at":"2026-07-22T22:23:57Z","subjects":["C. elegans","Proteostasis","Aging","Neurotransmitter signalling","RNA-Seq","Behaviour"],"languages":["en"],"rights":[],"rights_urls":["https://www.repository.cam.ac.uk/bitstreams/56756d99-332c-4b75-bb88-242cad4838fa/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.46618","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Taylor, Rebecca"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["LMB Cambridge Scholarship"]},{"key":"dc:creator","label":"Author","values":["Ozbey, Nesem Petek"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2019-12-04"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/299545"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["C. elegans","Proteostasis","Aging","Neurotransmitter signalling","RNA-Seq","Behaviour"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["https://www.repository.cam.ac.uk/bitstreams/56756d99-332c-4b75-bb88-242cad4838fa/download","https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.46618"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://www.repository.cam.ac.uk/bitstreams/57f50d3c-3c4d-4c16-a388-64ca88921b64/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The nervous system of C. elegans plays a role in the orchestration of systemic stress responses. 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We identified lysosomal gene upregulation in the intestine, which leads to activation of intestinal lysosomes downstream of neuronal xbp-1s. Moreover, comparison of cell autonomous and cell non-autonomous targets of XBP-1s within the intestine showed that XBP-1s has different but overlapping sets of target genes via different activation mechanisms. We also employed a candidate screening approach based on our previous finding that neurotransmitter secretion is required for intestinal UPRER activation upon neuronal xbp-1s overexpression, and identified positive and negative regulators of intestinal UPRER activation. This showed that distal UPRER activation relies on tyramine/octopamine production, and is modulated by the worm TGF-β homologue DAF-7. We then asked whether neuronal xbp-1s can affect other systemic outputs requiring neuron-specific functions, such as the regulation of behaviour. We found that a branch of the neuronal circuitry required to activate UPRER in the intestine following neuronal XBP-1s overexpression is also required to generate neuronal xbp-1s-dependent behavioural phenotypes in food-leaving and reproduction. These findings suggest that inter-tissue UPRER activation, increased longevity and healthspan can be coordinately regulated with stress-responsive behaviour by the activation of XBP-1s in the nervous system."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["580ea408272914e47edada4145605590","87eda9de84448d1f82354d60eee3eb5f"]},{"key":"dc:title","label":"Title","values":["Exploring the role of the unfolded protein response in C. elegans neurons"]}]}],"canonical_facts":{"dc:contributor.advisor":["Taylor, Rebecca"],"dc:contributor.sponsor":["LMB Cambridge Scholarship"],"dc:creator":["Ozbey, Nesem Petek"],"dc:date.issued":["2019-12-04"],"dc:description.abstract":["The nervous system of C. elegans plays a role in the orchestration of systemic stress responses. One of these stress responses, the unfolded protein response of the endoplasmic reticulum (UPRER), is activated to re-establish protein homeostasis (proteostasis) upon the detection of ER stress. Overexpression of active, spliced XBP-1 (XBP-1s), a transcription factor that acts downstream of the UPRER kinase/endoribonuclease IRE-1, in the nervous system of C. elegans increases the lifespan and healthspan of worms through UPRER induction in the intestine cell non-autonomously. To investigate XBP-1s-dependent changes in the nervous system of these animals, we conducted tissue-specific RNA-Seq in neurons. This approach allowed us to characterise differentially regulated neuronal and synaptic components, which may mediate changes to the nervous system that cause the release of inter-tissue UPRER-activating signals. Furthermore, we extended our tissue-specific RNA-Seq analyses to the intestine, using intestinal cells from neuronal xbp-1s- or intestinal xbp-1s-overexpressing worms. We identified lysosomal gene upregulation in the intestine, which leads to activation of intestinal lysosomes downstream of neuronal xbp-1s. Moreover, comparison of cell autonomous and cell non-autonomous targets of XBP-1s within the intestine showed that XBP-1s has different but overlapping sets of target genes via different activation mechanisms. We also employed a candidate screening approach based on our previous finding that neurotransmitter secretion is required for intestinal UPRER activation upon neuronal xbp-1s overexpression, and identified positive and negative regulators of intestinal UPRER activation. This showed that distal UPRER activation relies on tyramine/octopamine production, and is modulated by the worm TGF-β homologue DAF-7. We then asked whether neuronal xbp-1s can affect other systemic outputs requiring neuron-specific functions, such as the regulation of behaviour. We found that a branch of the neuronal circuitry required to activate UPRER in the intestine following neuronal XBP-1s overexpression is also required to generate neuronal xbp-1s-dependent behavioural phenotypes in food-leaving and reproduction. These findings suggest that inter-tissue UPRER activation, increased longevity and healthspan can be coordinately regulated with stress-responsive behaviour by the activation of XBP-1s in the nervous system."],"dc:format.checksum.md5":["580ea408272914e47edada4145605590","87eda9de84448d1f82354d60eee3eb5f"],"dc:identifier.doi":["10.17863/CAM.46618"],"dc:identifier.uri":["https://www.repository.cam.ac.uk/bitstreams/57f50d3c-3c4d-4c16-a388-64ca88921b64/download"],"dc:language":["en"],"dc:publisher.institution":["University of Cambridge"],"dc:relation.isreferencedby.uri":["https://www.repository.cam.ac.uk/handle/1810/299545"],"dc:rights":["https://www.repository.cam.ac.uk/bitstreams/56756d99-332c-4b75-bb88-242cad4838fa/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"dc:subject":["C. elegans","Proteostasis","Aging","Neurotransmitter signalling","RNA-Seq","Behaviour"],"dc:title":["Exploring the role of the unfolded protein response in C. elegans neurons"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-22T22:23:57Z"}