title: A chromosome 16p13.11 microduplication causes hyperactivity through dysregulation of miR-484/protocadherin-19 signaling.
abstract: Chromosome 16p13.11 microduplication is a risk factor associated with various neurodevelopmental disorders such as attention-deficit/hyperactivity disorder, intellectual disabilities, developmental delay and autistic spectrum disorder. The underlying molecular mechanism of this genetic variation remained unknown, but its core genetic locus-conserved across mice and humans-contains seven genes. Here, we generated bacterial artificial chromosome-transgenic mice carrying a human 16p13.11 locus, and these mice showed the behavioral hyperactivity phenotype. We identified miR-484 as the responsible gene using a combination of expression and functional analyses. Mature miR-484 was expressed during active cortical neurogenesis, and overexpression of miR-484 decreased proliferation and increased neural progenitor differentiation in vivo. Luciferase screening identified the 3'-untranslated region of protocadherin-19 (Pcdh19) as a target of miR-484. The effect of miR-484 on neurogenesis was rescued by ectopic PCDH19 expression. These results demonstrate that miR-484 promotes neurogenesis by inhibiting PCDH19. Dysregulation of neurogenesis by imbalanced miR-484/PCDH19 expression contributes to the pathogenesis of 16p13.11 microduplication syndrome.
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan.|Japan Science and Technology Agency, CREST, 5, Sanbancho, Chiyoda-ku, Japan.|Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Japan.|Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fujitani
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan.|Japan Science and Technology Agency, CREST, 5, Sanbancho, Chiyoda-ku, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan.|Japan Science and Technology Agency, CREST, 5, Sanbancho, Chiyoda-ku, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Fujiki
authors.affiliation: Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Fujihara
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan.|Japan Science and Technology Agency, CREST, 5, Sanbancho, Chiyoda-ku, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics; D020440:Gene Duplication / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D006948:Hyperkinesis; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics; D000091363:Protocadherins; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics
chemical_list: D015820:Cadherins; C572386:MIRN484 microRNA, human; D035683:MicroRNAs; C438605:PCDH19 protein, human; D000091363:Protocadherins