title: Transgenic expression of microRNA-185 causes a developmental arrest of T cells by targeting multiple genes including Mzb1.
abstract: miR-185 is a microRNA (miR) that targets Bruton's tyrosine kinase in B cells, with reductions in miR-185 linked to B cell autoantibody production. In hippocampal neurons, miR-185 targets both sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and a novel Golgi inhibitor. This miR is haploinsufficient in 90-95% of individuals with chromosome 22q11.2 deletion syndrome, patients who can present with immune, cardiac, and parathyroid problems, learning disorders, and a high incidence of schizophrenia in adults. The reduced levels of miR-185 in neurons cause presynaptic neurotransmitter release. Many of the 22q11.2 deletion syndrome patients have a thymic hypoplasia, which results in a peripheral T cell lymphopenia and unusual T helper cell skewing. The molecular targets of miR-185 in thymocytes are unknown. Using an miR-185 T cell transgenic approach, increasing levels of miR-185 attenuated T cell development at the T cell receptor β (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, whereas a knockdown of miR-185 diminished these calcium responses. These effects concur with reductions in Mzb1, an endoplasmic reticulum calcium regulator. Consistent with their haploinsufficiency of miR-185, Mzb1 levels were elevated in thymocyte extracts from several 22q11.2 deletion syndrome patients. Our findings indicate that miR-185 regulates T cell development through its targeting of several mRNAs including Mzb1.
authors.affiliation: From the Departments of Immunology.
authors.forename: Serkan
authors.initials: S
authors.lastname: Belkaya
authors.affiliation: From the Departments of Immunology.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Murray
authors.affiliation: From the Departments of Immunology.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Eitson
authors.affiliation: Pediatrics, and; the Children's Medical Center, Dallas, Texas 75235.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: de la Morena
authors.affiliation: From the Departments of Immunology.
authors.forename: James A
authors.initials: JA
authors.lastname: Forman
authors.affiliation: From the Departments of Immunology,; Pediatrics, and; Microbiology, the University of Texas Southwestern Medical Center, Dallas, Texas 75390-9093 and. Electronic address: nicolai.vanoers@utsouthwestern.edu.
authors.forename: Nicolai S C
authors.initials: NSC
authors.lastname: van Oers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D020013:Calcium Signaling; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D060168:Thymocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C570497:MEDA-7 protein, mouse; C552431:MIRN185 microRNA, human; C434482:MZB1 protein, human; D035683:MicroRNAs; C578934:Mirn185 microRNA, mouse; D050778:NFATC Transcription Factors; C494008:NFATC3 protein, human; C494009:Nfatc3 protein, mouse; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse; D002118:Calcium
keywords: 22q11.2 Deletion Syndrome; Calcium Intracellular Release; Genetic Diseases; Immunodeficiency; MicroRNA; T Cell Biology; Transcription Target Genes; Transgenic Mice