{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/1422"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/1422","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Characterization of Stress Responsive MicroRNAs and Their Roles in T Cell Development","abstract":"Physiological stress evokes rapid changes in both the innate and adaptive immune responses. Immature αβ T cells developing in the thymus are particularly sensitive to stress, with infections and/or exposure to lipopolysaccharide or glucocorticoids eliciting a rapid apoptotic program. MicroRNAs (miRs) are short, non-coding RNAs that play critical roles in the immune system by targeting diverse mRNAs. We hypothesized that a subset of thymically encoded miRs would be stress responsive and modulate thymopoiesis. Thymic miR profiling revealed 18 distinct miRs that are dysregulated more than 1.5-fold in response to lipopolysaccharide or the synthetic glucocorticoid dexamethasone. These stress-responsive miRs are dynamically regulated in distinct thymocyte subsets. We utilized both transgenic and gene-targeting approaches to study the impact of these miRs on thymopoiesis under normal and stress conditions. MiR-181d is the most down-regulated thymic miR in response to stress. The over-expression of miR-181d in developing thymocytes reduced the number of immature CD4+CD8+ thymocytes. Lipopolysaccharide or dexamethasone injections caused a 4-fold greater loss of these cells than in the wild type controls. The targeted elimination of miR-181d resulted in a thymus stress-responsiveness similar to wild-type mice, suggesting a functional redundancy between miR-181 family members. Gene expression comparisons further indicated that miR-181d affects a number of stress, metabolic, and signaling pathways. These findings demonstrate that selected miRs enhance stress-mediated thymic involution in vivo. MiR-185, another stress-responsive miR in murine thymus, is haploinsufficient in almost all individuals with 22q11.2 deletion/DiGeorge syndrome that can present with immune, cardiac, parathyroid, and psychological problems. The molecular targets of miR-185 in thymocytes are unknown. Transgenic expression of miR-185 attenuated thymopoiesis at the TCRβ-selection checkpoint and during positive selection. This caused a peripheral T cell lymphopenia. Mzb1, NFATc3, and Camk4 were identified as novel miR-185 targets. Elevations in miR-185 enhanced TCR-dependent intracellular calcium levels, while a knockdown of miR-185 diminished these calcium responses. These effects concur with reductions in Mzb1, an endoplasmic reticulum calcium regulator. Consistent with the haploinsufficiency of miR-185, Mzb1 levels were elevated in thymocyte extracts from several 22q11.2 deletion/DiGeorge syndrome patients. These findings indicate that miR-185 regulates T cell development through its targeting of several mRNAs including Mzb1.","abstract_html":"Physiological stress evokes rapid changes in both the innate and adaptive immune responses. Immature αβ T cells developing in the thymus are particularly sensitive to stress, with infections and/or exposure to lipopolysaccharide or glucocorticoids eliciting a rapid apoptotic program. MicroRNAs (miRs) are short, non-coding RNAs that play critical roles in the immune system by targeting diverse mRNAs. We hypothesized that a subset of thymically encoded miRs would be stress responsive and modulate thymopoiesis. Thymic miR profiling revealed 18 distinct miRs that are dysregulated more than 1.5-fold in response to lipopolysaccharide or the synthetic glucocorticoid dexamethasone. These stress-responsive miRs are dynamically regulated in distinct thymocyte subsets. We utilized both transgenic and gene-targeting approaches to study the impact of these miRs on thymopoiesis under normal and stress conditions. MiR-181d is the most down-regulated thymic miR in response to stress. The over-expression of miR-181d in developing thymocytes reduced the number of immature CD4+CD8+ thymocytes. Lipopolysaccharide or dexamethasone injections caused a 4-fold greater loss of these cells than in the wild type controls. The targeted elimination of miR-181d resulted in a thymus stress-responsiveness similar to wild-type mice, suggesting a functional redundancy between miR-181 family members. Gene expression comparisons further indicated that miR-181d affects a number of stress, metabolic, and signaling pathways. These findings demonstrate that selected miRs enhance stress-mediated thymic involution in vivo. MiR-185, another stress-responsive miR in murine thymus, is haploinsufficient in almost all individuals with 22q11.2 deletion/DiGeorge syndrome that can present with immune, cardiac, parathyroid, and psychological problems. The molecular targets of miR-185 in thymocytes are unknown. Transgenic expression of miR-185 attenuated thymopoiesis at the TCRβ-selection checkpoint and during positive selection. This caused a peripheral T cell lymphopenia. Mzb1, NFATc3, and Camk4 were identified as novel miR-185 targets. Elevations in miR-185 enhanced TCR-dependent intracellular calcium levels, while a knockdown of miR-185 diminished these calcium responses. These effects concur with reductions in Mzb1, an endoplasmic reticulum calcium regulator. Consistent with the haploinsufficiency of miR-185, Mzb1 levels were elevated in thymocyte extracts from several 22q11.2 deletion/DiGeorge syndrome patients. These findings indicate that miR-185 regulates T cell development through its targeting of several mRNAs including Mzb1.","abstract_has_math":false,"creators":["Belkaya, Serkan"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Hooper, Lora V.","van Oers, Nicolai S. C.","Chen, Zhijian J.","Yarovinsky, Felix","Liou, Jen"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-06-10T19:40:34Z","date_published":"2014-06-10T19:40:34Z","updated_at":"2026-07-24T05:52:13Z","subjects":["MicroRNAs","Stress, Physiological","T-Lymphocytes"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["885267264"],"render_values":[{"text":"885267264","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/1422","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Hooper, Lora V.","van Oers, Nicolai S. 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Immature αβ T cells developing in the thymus are particularly sensitive to stress, with infections and/or exposure to lipopolysaccharide or glucocorticoids eliciting a rapid apoptotic program. MicroRNAs (miRs) are short, non-coding RNAs that play critical roles in the immune system by targeting diverse mRNAs. We hypothesized that a subset of thymically encoded miRs would be stress responsive and modulate thymopoiesis. Thymic miR profiling revealed 18 distinct miRs that are dysregulated more than 1.5-fold in response to lipopolysaccharide or the synthetic glucocorticoid dexamethasone. These stress-responsive miRs are dynamically regulated in distinct thymocyte subsets. We utilized both transgenic and gene-targeting approaches to study the impact of these miRs on thymopoiesis under normal and stress conditions. MiR-181d is the most down-regulated thymic miR in response to stress. The over-expression of miR-181d in developing thymocytes reduced the number of immature CD4+CD8+ thymocytes. Lipopolysaccharide or dexamethasone injections caused a 4-fold greater loss of these cells than in the wild type controls. The targeted elimination of miR-181d resulted in a thymus stress-responsiveness similar to wild-type mice, suggesting a functional redundancy between miR-181 family members. Gene expression comparisons further indicated that miR-181d affects a number of stress, metabolic, and signaling pathways. These findings demonstrate that selected miRs enhance stress-mediated thymic involution in vivo. MiR-185, another stress-responsive miR in murine thymus, is haploinsufficient in almost all individuals with 22q11.2 deletion/DiGeorge syndrome that can present with immune, cardiac, parathyroid, and psychological problems. The molecular targets of miR-185 in thymocytes are unknown. Transgenic expression of miR-185 attenuated thymopoiesis at the TCRβ-selection checkpoint and during positive selection. This caused a peripheral T cell lymphopenia. Mzb1, NFATc3, and Camk4 were identified as novel miR-185 targets. Elevations in miR-185 enhanced TCR-dependent intracellular calcium levels, while a knockdown of miR-185 diminished these calcium responses. These effects concur with reductions in Mzb1, an endoplasmic reticulum calcium regulator. Consistent with the haploinsufficiency of miR-185, Mzb1 levels were elevated in thymocyte extracts from several 22q11.2 deletion/DiGeorge syndrome patients. These findings indicate that miR-185 regulates T cell development through its targeting of several mRNAs including Mzb1."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Characterization of Stress Responsive MicroRNAs and Their Roles in T Cell Development"]}]}],"canonical_facts":{"dc:contributor":["Hooper, Lora V.","van Oers, Nicolai S. C.","Chen, Zhijian J.","Yarovinsky, Felix","Liou, Jen"],"dc:creator":["Belkaya, Serkan"],"dc:date":["2014-06-10T19:40:34Z","2014-05","2014-01-06","May 2014","2014-06-10T19:36:04Z"],"dc:description":["Physiological stress evokes rapid changes in both the innate and adaptive immune responses. Immature αβ T cells developing in the thymus are particularly sensitive to stress, with infections and/or exposure to lipopolysaccharide or glucocorticoids eliciting a rapid apoptotic program. MicroRNAs (miRs) are short, non-coding RNAs that play critical roles in the immune system by targeting diverse mRNAs. We hypothesized that a subset of thymically encoded miRs would be stress responsive and modulate thymopoiesis. Thymic miR profiling revealed 18 distinct miRs that are dysregulated more than 1.5-fold in response to lipopolysaccharide or the synthetic glucocorticoid dexamethasone. These stress-responsive miRs are dynamically regulated in distinct thymocyte subsets. We utilized both transgenic and gene-targeting approaches to study the impact of these miRs on thymopoiesis under normal and stress conditions. MiR-181d is the most down-regulated thymic miR in response to stress. The over-expression of miR-181d in developing thymocytes reduced the number of immature CD4+CD8+ thymocytes. Lipopolysaccharide or dexamethasone injections caused a 4-fold greater loss of these cells than in the wild type controls. The targeted elimination of miR-181d resulted in a thymus stress-responsiveness similar to wild-type mice, suggesting a functional redundancy between miR-181 family members. Gene expression comparisons further indicated that miR-181d affects a number of stress, metabolic, and signaling pathways. These findings demonstrate that selected miRs enhance stress-mediated thymic involution in vivo. MiR-185, another stress-responsive miR in murine thymus, is haploinsufficient in almost all individuals with 22q11.2 deletion/DiGeorge syndrome that can present with immune, cardiac, parathyroid, and psychological problems. The molecular targets of miR-185 in thymocytes are unknown. Transgenic expression of miR-185 attenuated thymopoiesis at the TCRβ-selection checkpoint and during positive selection. This caused a peripheral T cell lymphopenia. Mzb1, NFATc3, and Camk4 were identified as novel miR-185 targets. Elevations in miR-185 enhanced TCR-dependent intracellular calcium levels, while a knockdown of miR-185 diminished these calcium responses. These effects concur with reductions in Mzb1, an endoplasmic reticulum calcium regulator. Consistent with the haploinsufficiency of miR-185, Mzb1 levels were elevated in thymocyte extracts from several 22q11.2 deletion/DiGeorge syndrome patients. These findings indicate that miR-185 regulates T cell development through its targeting of several mRNAs including Mzb1."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/1422","885267264"],"dc:language":["en"],"dc:subject":["MicroRNAs","Stress, Physiological","T-Lymphocytes"],"dc:title":["Characterization of Stress Responsive MicroRNAs and Their Roles in T Cell Development"],"dc:type":["Thesis","Text"]},"updated_at":"2026-07-24T05:52:13Z"}