title: Transgenic expression of microRNA-181d augments the stress-sensitivity of CD4(+)CD8(+) thymocytes.
abstract: Physiological stress resulting from infections, trauma, surgery, alcoholism, malnutrition, and/or pregnancy results in a substantial depletion of immature CD4(+)CD8(+) thymocytes. We previously identified 18 distinct stress-responsive microRNAs (miRs) in the thymus upon systemic stress induced by lipopolysaccharide (LPS) or the synthetic glucocorticoid, dexamethasone (Dex). MiRs are short, non-coding RNAs that play critical roles in the immune system by targeting diverse mRNAs, suggesting that their modulation in the thymus in response to stress could impact thymopoiesis. MiR-181d is one such stress-responsive miR, exhibiting a 15-fold down-regulation in expression. We utilized both transgenic and gene-targeting approaches to study the impact of miR-181d on thymopoiesis under normal and stress conditions. The over-expression of miR-181d in developing thymocytes reduced the total number of immature CD4(+)CD8(+) thymocytes. LPS or Dex injections caused a 4-fold greater loss of these cells when compared with the wild type controls. A knockout mouse was developed to selectively eliminate miR-181d, leaving the closely spaced and contiguous family member miR-181c intact. The targeted elimination of just miR-181d resulted in a thymus stress-responsiveness similar to wild-type mice. These experiments suggest that one or more of three other miR-181 family members have overlapping or compensatory functions. Gene expression comparisons of thymocytes from the wild type versus transgenic mice indicated that miR-181d targets a number of stress, metabolic, and signaling pathways. These findings demonstrate that selected miRs enhance stress-mediated thymic involution in vivo.
authors.affiliation: Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Serkan
authors.initials: S
authors.lastname: Belkaya
authors.affiliation: Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America ; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America ; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Nicolai S C
authors.initials: NS
authors.lastname: van Oers
mesh_terms: D000818:Animals; D001483:Base Sequence; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D008969:Molecular Sequence Data; D061251:Primary Cell Culture; D013312:Stress, Physiological; D060168:Thymocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D008070:Lipopolysaccharides; D035683:MicroRNAs; C529100:mirn181 microRNA, mouse; D003907:Dexamethasone