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Molecular Neurobiology

, Volume 54, Issue 5, pp 3439–3452 | Cite as

MicroRNA-338 Attenuates Cortical Neuronal Outgrowth by Modulating the Expression of Axon Guidance Genes

  • Aron Kos
  • Teun Klein-Gunnewiek
  • Julia Meinhardt
  • Nikkie F. M. Olde Loohuis
  • Hans van Bokhoven
  • Barry B. Kaplan
  • Gerard J. Martens
  • Sharon M. Kolk
  • Armaz AschrafiEmail author
Article

Abstract

MicroRNAs (miRs) are small non-coding RNAs that confer robustness to gene networks through post-transcriptional gene regulation. Previously, we identified miR-338 as a modulator of axonal outgrowth in sympathetic neurons. In the current study, we examined the role of miR-338 in the development of cortical neurons and uncovered its downstream mRNA targets. Long-term inhibition of miR-338 during neuronal differentiation resulted in reduced dendritic complexity and altered dendritic spine morphology. Furthermore, monitoring axon outgrowth in cortical cells revealed that miR-338 overexpression decreased, whereas inhibition of miR-338 increased axonal length. To identify gene targets mediating the observed phenotype, we inhibited miR-338 in cortical neurons and performed whole-transcriptome analysis. Pathway analysis revealed that miR-338 modulates a subset of transcripts involved in the axonal guidance machinery by means of direct and indirect gene targeting. Collectively, our results implicate miR-338 as a novel regulator of cortical neuronal maturation by fine-tuning the expression of gene networks governing cortical outgrowth.

Keywords

MicroRNA Cortex Neurodevelopment Neurite development Robo2 

Notes

Acknowledgments

We thank N van Bakel, D Versteegden and M van Kessel for technical assistance. We thank the RIMLS microscopy platform (http://ncmls.nl/technology-platform/microscope-imaging-centre/) for support and maintenance of the equipment. The research of the authors is supported by grants from the “Donders Center for Neuroscience fellowship award of the Radboudumc” [to A. A.]; the “FP7-Marie Curie International Reintegration Grant” [to A. A. grant number 276868] and GENCODYS, an EU FP7 large-scale integrating project grant [Grant number 241995] [to HvB].

Compliance with Ethical Standards

All animal use, care and experiments were performed according to protocols approved by the Committee for Animal Experiments of the Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Conflict of Interest

The authors declare no competing financial interests.

Supplementary material

12035_2016_9925_MOESM1_ESM.xlsx (39 kb)
ESM 1 (XLSX 39 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Aron Kos
    • 1
    • 2
  • Teun Klein-Gunnewiek
    • 1
    • 2
  • Julia Meinhardt
    • 1
    • 2
  • Nikkie F. M. Olde Loohuis
    • 1
    • 2
  • Hans van Bokhoven
    • 1
    • 3
    • 2
  • Barry B. Kaplan
    • 4
  • Gerard J. Martens
    • 5
    • 2
  • Sharon M. Kolk
    • 5
    • 2
  • Armaz Aschrafi
    • 2
    • 4
    Email author
  1. 1.Department of Cognitive NeuroscienceRadboud university medical centerNijmegenThe Netherlands
  2. 2.Donders Institute for Brain, Cognition, and Behaviour, Centre for NeuroscienceNijmegenThe Netherlands
  3. 3.Department of Human GeneticsRadboud university medical centerNijmegenThe Netherlands
  4. 4.Laboratory of Molecular Biology, National Institute of Mental HealthNational Institutes of HealthBethesdaUSA
  5. 5.Department of Molecular Animal PhysiologyRadboud UniversityNijmegenThe Netherlands

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