title: Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion.
abstract: 22q11.2 microdeletions result in specific cognitive deficits and schizophrenia. Analysis of Df(16)A(+/-) mice, which model this microdeletion, revealed abnormalities in the formation of neuronal dendrites and spines, as well as altered brain microRNAs. Here, we show a drastic reduction of miR-185, which resides within the 22q11.2 locus, to levels more than expected by a hemizygous deletion, and we demonstrate that this reduction alters dendritic and spine development. miR-185 represses, through an evolutionarily conserved target site, a previously unknown inhibitor of these processes that resides in the Golgi apparatus and shows higher prenatal brain expression. Sustained derepression of this inhibitor after birth represents the most robust transcriptional disturbance in the brains of Df(16)A(+/-) mice and results in structural alterations in the hippocampus. Reduction of miR-185 also has milder age- and region-specific effects on the expression of some Golgi-related genes. Our findings illuminate the contribution of microRNAs in psychiatric disorders and cognitive dysfunction.
authors: Department of Psychiatry, College of Physicians and Surgeons, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA.
authors: Bin
authors: B
authors: Xu
authors: Pei-Ken
authors: PK
authors: Hsu
authors: Kimberly L
authors: KL
authors: Stark
authors: Maria
authors: M
authors: Karayiorgou
authors: Joseph A
authors: JA
authors: Gogos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins
chemical_list: C474044:Dgcr8 protein, mouse; C543592:EMC10 protein, human; C578933:Emc10 protein, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; C578934:Mirn185 microRNA, mouse; D011506:Proteins; D016601:RNA-Binding Proteins