title: miR-128 regulates neuronal migration, outgrowth and intrinsic excitability via the intellectual disability gene Phf6.
abstract: miR-128, a brain-enriched microRNA, has been implicated in the control of neurogenesis and synaptogenesis but its potential roles in intervening processes have not been addressed. We show that post-transcriptional mechanisms restrict miR-128 accumulation to post-mitotic neurons during mouse corticogenesis and in adult stem cell niches. Whereas premature miR-128 expression in progenitors for upper layer neurons leads to impaired neuronal migration and inappropriate branching, sponge-mediated inhibition results in overmigration. Within the upper layers, premature miR-128 expression reduces the complexity of dendritic arborization, associated with altered electrophysiological properties. We show that Phf6, a gene mutated in the cognitive disorder Börjeson-Forssman-Lehmann syndrome, is an important regulatory target for miR-128. Restoring PHF6 expression counteracts the deleterious effect of miR-128 on neuronal migration, outgrowth and intrinsic physiological properties. Our results place miR-128 upstream of PHF6 in a pathway vital for cortical lamination as well as for the development of neuronal morphology and intrinsic excitability.
authors.affiliation: Institute for Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Franzoni
authors.affiliation: Institute for Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sam A
authors.initials: SA
authors.lastname: Booker
authors.affiliation: Institute for Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Parthasarathy
authors.affiliation: Institute for Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Frederick
authors.initials: F
authors.lastname: Rehfeld
authors.affiliation: Institute for Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Grosser
authors.affiliation: Institute for Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Swathi
authors.initials: S
authors.lastname: Srivatsa
authors.affiliation: Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Heiko R
authors.initials: HR
authors.lastname: Fuchs
authors.affiliation: Institute for Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Victor
authors.initials: V
authors.lastname: Tarabykin
authors.affiliation: Institute for Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Imre
authors.initials: I
authors.lastname: Vida
authors.affiliation: Institute for Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: F Gregory
authors.initials: FG
authors.lastname: Wulczyn
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D048430:Cell Shape; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D004827:Epilepsy / Q000235:genetics; D005145:Face / Q000002:abnormalities; D005385:Fingers / Q000002:abnormalities; D018507:Gene Expression Regulation, Developmental; D006130:Growth Disorders / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007006:Hypogonadism / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics*; D038901:X-Linked Intellectual Disability / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D009765:Obesity / Q000235:genetics; D012322:RNA Precursors / Q000378:metabolism; D012097:Repressor Proteins; D055153:Stem Cell Niche; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; D035683:MicroRNAs; C550324:Mirn128 microRNA, mouse; C526788:Phf6 protein, mouse; D012322:RNA Precursors; D012097:Repressor Proteins
keywords: Börjeson-Forssman-Lehmann syndrome; cell biology; cortical development; developmental biology; developmental timing; mouse; post-translational gene regulation; stem cells