Overexpression of miR-128 specifically inhibits the truncated isoform of NTRK3 and upregulates BCL2 in SH-SY5Y neuroblastoma cells

Monica Guidi, Margarita Muiños-Gimeno, Birgit Kagerbauer, Eulàlia Martí, Xavier P. Estivill, Yolanda Espinosa-Parrilla

Research output: Contribution to journalArticle

53 Citations (Scopus)

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.

Original languageEnglish
Article number95
JournalBMC Molecular Biology
Volume11
DOIs
Publication statusPublished - 10 Dec 2010
Externally publishedYes

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MicroRNAs
Neuroblastoma
Protein Isoforms
Up-Regulation
Cell Survival
trkC Receptor
Nerve Growth Factor Receptors
Small Untranslated RNA
Neuronal Plasticity
Nerve Growth Factors
3' Untranslated Regions
Gene Expression Profiling
Nervous System
Small Interfering RNA
Genes
Cell Death
Phosphotransferases
Cell Count
Cell Proliferation
Apoptosis

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Overexpression of miR-128 specifically inhibits the truncated isoform of NTRK3 and upregulates BCL2 in SH-SY5Y neuroblastoma cells. / Guidi, Monica; Muiños-Gimeno, Margarita; Kagerbauer, Birgit; Martí, Eulàlia; Estivill, Xavier P.; Espinosa-Parrilla, Yolanda.

In: BMC Molecular Biology, Vol. 11, 95, 10.12.2010.

Research output: Contribution to journalArticle

Guidi, Monica ; Muiños-Gimeno, Margarita ; Kagerbauer, Birgit ; Martí, Eulàlia ; Estivill, Xavier P. ; Espinosa-Parrilla, Yolanda. / Overexpression of miR-128 specifically inhibits the truncated isoform of NTRK3 and upregulates BCL2 in SH-SY5Y neuroblastoma cells. In: BMC Molecular Biology. 2010 ; Vol. 11.
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AU - Guidi, Monica

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AU - Estivill, Xavier P.

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AB - 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.

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