title: Overexpression of miR-128 specifically inhibits the truncated isoform of NTRK3 and upregulates BCL2 in SH-SY5Y neuroblastoma cells.
abstract: BACKGROUND
  Neurotrophins and their receptors are key molecules in the regulation of neuronal differentiation and survival. They mediate the survival of neurons during development and adulthood and are implicated in synaptic plasticity. The human neurotrophin-3 receptor gene NTRK3 yields two major isoforms, a full-length kinase-active form and a truncated non-catalytic form, which activates a specific pathway affecting membrane remodeling and cytoskeletal reorganization. The two variants present non-overlapping 3'UTRs, indicating that they might be differentially regulated at the post-transcriptional level. Here, we provide evidence that the two isoforms of NTRK3 are targeted by different sets of microRNAs, small non-coding RNAs that play an important regulatory role in the nervous system.
  
  
  RESULTS
  We identify one microRNA (miR-151-3p) that represses the full-length isoform of NTRK3 and four microRNAs (miR-128, miR-485-3p, miR-765 and miR-768-5p) that repress the truncated isoform. In particular, we show that the overexpression of miR-128 - a brain enriched miRNA - causes morphological changes in SH-SY5Y neuroblastoma cells similar to those observed using an siRNA specifically directed against truncated NTRK3, as well as a significant increase in cell number. Accordingly, transcriptome analysis of cells transfected with miR-128 revealed an alteration of the expression of genes implicated in cytoskeletal organization as well as genes involved in apoptosis, cell survival and proliferation, including the anti-apoptotic factor BCL2.
  
  
  CONCLUSIONS
  Our results show that the regulation of NTRK3 by microRNAs is isoform-specific and suggest that neurotrophin-mediated processes are strongly linked to microRNA-dependent mechanisms. In addition, these findings open new perspectives for the study of the physiological role of miR-128 and its possible involvement in cell death/survival processes.
authors.affiliation: Center for Genomic Regulation, Genes and Disease Program, Dr, Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Guidi
authors.forename: Margarita
authors.initials: M
authors.lastname: Muiños-Gimeno
authors.forename: Birgit
authors.initials: B
authors.lastname: Kagerbauer
authors.forename: Eulàlia
authors.initials: E
authors.lastname: Martí
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Espinosa-Parrilla
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D019295:Computational Biology; D020869:Gene Expression Profiling; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D020812:Receptor, trkC / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C545189:MIRN128 microRNA, human; C000600151:MIRN765 microRNA, human; D035683:MicroRNAs; D009414:Nerve Growth Factors; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D020812:Receptor, trkC