title: miR-1, miR-10b, miR-155, and miR-191 are novel regulators of BDNF.
abstract: Brain-derived neurotrophic factor (BDNF) is a secreted protein of the neurotrophin family that regulates brain development, synaptogenesis, memory and learning, as well as development of peripheral organs, such as angiogenesis in the heart and postnatal growth and repair of skeletal muscle. However, while precise regulation of BDNF levels is an important determinant in defining the biological outcome, the role of microRNAs (miRs) in modulating BDNF expression has not been extensively analyzed. Using in silico approaches, reporter systems, and analysis of endogenous BDNF, we show that miR-1, miR-10b, miR-155, and miR-191 directly repress BDNF through binding to their predicted sites in BDNF 3'UTR. We find that the overexpression of miR-1 and miR-10b suppresses endogenous BDNF protein levels and that silencing endogenous miR-10b increases BDNF mRNA and protein levels. Furthermore, we show that miR-1/206 binding sites within BDNF 3'UTR are used in differentiated myotubes but not in undifferentiated myoblasts. Finally, our data from two cell lines suggest that endogenous miR-1/206 and miR-10 family miRs act cooperatively in suppressing BDNF through their predicted sites in BDNF 3'UTR. In conclusion, our results highlight miR-1, miR-10b, miR-155, and miR-191 as novel regulators of BDNF long and short 3'UTR isoforms, supporting future research in different physiological and pathological contexts.
authors.affiliation: Institute of Biotechnology, University of Helsinki, 00014, Helsinki, Finland.
authors.forename: Kärt
authors.initials: K
authors.lastname: Varendi
authors.forename: Anmol
authors.initials: A
authors.lastname: Kumar
authors.forename: Mari-Anne
authors.initials: MA
authors.lastname: Härma
authors.forename: Jaan-Olle
authors.initials: JO
authors.lastname: Andressoo
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D020413:3' Untranslated Regions; D019208:Brain-Derived Neurotrophic Factor; C569259:MIRN10 microRNA, mouse; C555937:MIRN191 microRNA, mouse; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; C532623:Mirn155 microRNA, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger