title: Stage-specific modulation of cortical neuronal development by Mmu-miR-134.
abstract: To realize the potential of microRNAs (miRs) as fine-tuning regulators of embryonic neuronal differentiation, it is critical to define their developmental function. Mmu-miR-134 (miR-134) is a powerful inducer of pluripotent stem cell differentiation. However, its functional role during embryonic, neuronal development is unknown. We demonstrate that mature, miR-134 transcript levels elevate during embryonic, neuronal differentiation in vitro and in vivo. To define the developmental targets and function of miR-134, we identified multiple brain-expressed targets including the neural progenitor cell-enriched, bone morphogenetic protein (BMP) antagonist Chordin-like 1 (Chrdl-1) and the postmitotic, neuron-specific, microtubule-associated protein, Doublecortin (Dcx). We show that, through interaction with Dcx and/or Chrdl-1, miR-134 has stage-specific effects on cortical progenitors, migratory neurons, and differentiated neurons. In neural progenitors, miR-134 promotes cell proliferation and counteracts Chrdl-1-induced apoptosis and Dcx-induced differentiation in vitro. In neurons, miR-134 reduces cell migration in vitro and in vivo in a Dcx-dependent manner. In differentiating neurons, miR-134 modulates process outgrowth in response to exogenous BMP-4 in a noggin-reversible manner. Taken together, we present Dcx and Chrdl-1 as new regulatory targets of miR-134 during embryonic, mouse, cortical, and neuronal differentiation and show a novel and previously undiscovered role for miR-134 in the stage-specific modulation of cortical development.
authors.affiliation: Department of Stem Cell and Developmental Biology, A*STAR Genome Institute of Singapore 138672, Singapore. philip.gaughwin@med.lu.se
authors.forename: Philip
authors.initials: P
authors.lastname: Gaughwin
authors.forename: Maciej
authors.initials: M
authors.lastname: Ciesla
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.forename: Bing
authors.initials: B
authors.lastname: Lim
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018390:Gene Targeting / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology* / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism
chemical_list: C430597:Chrdl1 protein, mouse; C000714328:DCX protein, human; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005136:Eye Proteins; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; C551912:Mirn134 microRNA, mouse; D009419:Nerve Tissue Proteins; D009479:Neuropeptides