title: miR-218 is essential to establish motor neuron fate as a downstream effector of Isl1-Lhx3.
abstract: While microRNAs have emerged as an important component of gene regulatory networks, it remains unclear how microRNAs collaborate with transcription factors in the gene networks that determines neuronal cell fate. Here we show that in the developing spinal cord, the expression of miR-218 is directly upregulated by the Isl1-Lhx3 complex, which drives motor neuron fate. Inhibition of miR-218 suppresses the generation of motor neurons in both chick neural tube and mouse embryonic stem cells, suggesting that miR-218 plays a crucial role in motor neuron differentiation. Results from unbiased RISC-trap screens, in vivo reporter assays and overexpression studies indicated that miR-218 directly represses transcripts that promote developmental programs for interneurons. In addition, we found that miR-218 activity is required for Isl1-Lhx3 to effectively induce motor neurons and suppress interneuron fates. Together our results reveal an essential role of miR-218 as a downstream effector of the Isl1-Lhx3 complex in establishing motor neuron identity.
authors.affiliation: Department of Pediatrics, Pediatric Neuroscience Research Program, Papé Family Pediatric Research Institute, Portland, Oregon 97239, USA.
authors.forename: Karen P
authors.initials: KP
authors.lastname: Thiebes
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Heejin
authors.initials: H
authors.lastname: Nam
authors.affiliation: Vollum Institute, Portland, Oregon 97239, USA.
authors.forename: Xiaolu A
authors.initials: XA
authors.lastname: Cambronne
authors.affiliation: Vollum Institute, Portland, Oregon 97239, USA.
authors.forename: Rongkun
authors.initials: R
authors.lastname: Shen
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Glasgow
authors.affiliation: Department of Pediatrics, Pediatric Neuroscience Research Program, Papé Family Pediatric Research Institute, Portland, Oregon 97239, USA.|Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Medical School, Gwangju 501-746, Korea.
authors.forename: Hyong-Ho
authors.initials: HH
authors.lastname: Cho
authors.affiliation: Department of Pediatrics, Pediatric Neuroscience Research Program, Papé Family Pediatric Research Institute, Portland, Oregon 97239, USA.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Kwon
authors.affiliation: Vollum Institute, Portland, Oregon 97239, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Goodman
authors.affiliation: Department of Pediatrics, Pediatric Neuroscience Research Program, Papé Family Pediatric Research Institute, Portland, Oregon 97239, USA.|Department of Cell and Developmental Biology, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Jae W
authors.initials: JW
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Seunghee
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Pediatric Neuroscience Research Program, Papé Family Pediatric Research Institute, Portland, Oregon 97239, USA.|Vollum Institute, Portland, Oregon 97239, USA.|Department of Cell and Developmental Biology, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000818:Animals; D002642:Chick Embryo; D018274:Electroporation; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009046:Motor Neurons / Q000166:cytology*; D000066450:Mouse Embryonic Stem Cells; D054259:Neural Tube / Q000166:cytology / Q000196:embryology*; D055495:Neurogenesis / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D060850:LIM-Homeodomain Proteins; C094898:Lhx3 protein; C547471:MIRN218 microRNA, human; C547684:MIRN218 microRNA, mouse; D035683:MicroRNAs; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1