miR379–410 cluster miRNAs regulate neurogenesis and neuronal migration by fine‐tuning N‐cadherin

• Published in: The EMBO journal 2014-04, Vol.33 (8), p.906-920
• Main Authors: Rago, Luciano, Beattie, Robert, Taylor, Verdon, Winter, Jennifer
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - biosynthesis; Cadherins - biosynthesis; Cell adhesion & migration; Cell differentiation; Cell Movement; EMBO05; EMBO27; EMBO39; Gene Expression Regulation, Developmental; Mice; MicroRNAs; MicroRNAs - metabolism; neural differentiation; neural migration; Neural Stem Cells - physiology; Neurogenesis; Neurons; N‐cadherin; Stem cells
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1002/embj.201386591

N‐cadherin‐mediated adhesion is essential for maintaining the tissue architecture and stem cell niche in the developing neocortex. N‐cadherin expression level is precisely and dynamically controlled throughout development; however, the underlying regulatory mechanisms remain largely unknown. MicroRNAs (miRNAs) play an important role in the regulation of protein expression and subcellular localisation. In this study, we show that three miRNAs belonging to the miR379–410 cluster regulate N‐cadherin expression levels in neural stem cells and migrating neurons. The overexpression of these three miRNAs in radial glial cells repressed N‐cadherin expression and increased neural stem cell differentiation and neuronal migration. This phenotype was rescued when N‐cadherin was expressed from a miRNA‐insensitive construct. Transient abrogation of the miRNAs reduced stem cell differentiation and increased cell proliferation. The overexpression of these miRNAs specifically in newborn neurons delayed migration into the cortical plate, whereas the knockdown increased migration. Collectively, our results indicate a novel role for miRNAs of the miR379–410 cluster in the fine‐tuning of N‐cadherin expression level and in the regulation of neurogenesis and neuronal migration in the developing neocortex. Synopsis Members of the miR379–410 miRNA cluster control the proliferation and differentiation of radial glial cells (RGCs) and the migration of cortical neurons by reducing N‐cadherin levels in the developing neocortex. miR369‐3p, miR496 and miR543 are expressed in the mouse developing neocortex. miR369‐3p, miR496 and miR543 regulate the proliferation and differentiation of RGCs into cortical neurons. miR369‐3p, miR496 and miR543 control cortical neuron migration. miR369‐3p, miR496 and miR543 exert their effects via reduction of N‐cadherin expression in vitro and in vivo . Graphical Abstract Members of the miR379–410 miRNA cluster control the proliferation and differentiation of radial glial cells (RGCs) and the migration of cortical neurons by reducing N‐cadherin levels in the developing neocortex.