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Microrna Dysregulation in Neuropsychiatric Disorders and Cognitive Dysfunction MicroRNA Dysregulation in Neuropsychiatric Disorders and Cognitive Dysfunction Pei-Ken Hsu Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2012 © 2012 Pei-Ken Hsu All rights reserved ABSTRACT MicroRNA Dysregulation in Neuropsychiatric Disorders and Cognitive Dysfunction Pei-Ken Hsu MicroRNAs (miRNAs) are evolutionarily-conserved small non-coding RNAs that are important posttranscriptional regulators of gene expression. Genetic Variants may cause microRNA dysregulation and the concomitant aberrant target expression. The dysregulation of one or a few targets may in turn lead to functional consequences ranging from phenotypic variations to disease conditions. In this thesis, I present our studies of mouse models of two human genetic variants − a rare copy number variant (CNV), 22q11.2 microdeletions, and a common single nucleotide polymorphism (SNP), BDNF Val66Met . 22q11.2 microdeletions result in specific cognitive deficits and high risk to develop schizophrenia. Analysis of Df(16)A +/– mice, which model this microdeletion, revealed abnormalities in the formation of neuronal dendrites and spines as well as microRNA dysregulation in brain. 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 demonstrate that this reduction impairs dendritic and spine development. miR-185 targets and represses, through an evolutionary conserved target site, a previously unknown inhibitor of these processes that resides in the Golgi apparatus. Sustained derepression of this inhibitor after birth represents the most robust transcriptional disturbance in the brains of Df(16)A +/− mice and could affect the formation and maintenance of neural circuits. Reduction of miR-185 also has milder effects on the expression of a group of Golgi-related genes. One the other hand, BNDF Val66Met results in impaired activity-dependent secretion of BDNF from neuronal terminals and affects episodic memory and affective behaviors. We found a modest reduction of miR-146b which causes derepression of mRNA and/or protein levels of a few targets. Our findings add to the growing evidence of the pivotal involvement of miRNAs in the development of neuropsychiatric disorders and cognitive dysfunction. In addition, the identification of key players in miRNA dysregulation has implications for both basic and translational research in psychiatric disorders and cognitive dysfunction. Table of Contents Chapter I − Tiny Regulators with Profound Impact in Neuropsychiatric Disorders ix 1.1 MicroRNAs-mediated Regulation ..................................................................................................... 1 1.2 Altered microRNA Expression and Function in Neuropsychiatric Disorders ............................. 3 1.2.1 Schizophrenia .............................................................................................................................. 3 1.2.2 Autism Spectrum Disorders ......................................................................................................... 8 1.2.3 Rett Syndrome ........................................................................................................................... 10 1.2.4 Fragile X Syndrome ................................................................................................................... 12 1.2.5 Tourette's Syndrome .................................................................................................................. 13 1.2.6 Down Syndrome ........................................................................................................................ 14 1.3 Potential Mechanistic Connections between microRNA Dysregulation and Neuropsychiatric Disorders ........................................................................................................... 15 1.3.1 Insights from Global Disruption of miRNA Biogenesis and Action ............................................ 15 1.3.2 Individual miRNAs Modulate Dendritic Complexity and Spine Morphology in Neurons ............ 16 1.3.3 Individual miRNAs Modulate Neurogenesis, Neuronal Proliferation, Migration and Integration ................................................................................................................................. 18 1.3.4 Individual miRNAs Modulate Neuronal Electrophysiological Properties in Response to Neuronal Activity ....................................................................................................................... 20 1.4 Summary ........................................................................................................................................... 20 1.5 References ........................................................................................................................................ 24 Chapter II − A Major Downstream Effector of MicroRNA Dysregulation in 22q11.2 Genomic Losses ...................................................................... 36 2.1 Introduction ...................................................................................................................................... 36 2.1.1 22q11.2 Microdeletions and Schizophrenia ............................................................................... 36 2.1.2 A Mouse Model of 22q11.2 Microdeletion ................................................................................. 37 2.1.3 miRNA Dysregulation in of 22q11.2 Microdeletion Mouse Model ............................................. 39 2.1.4 In this Chapter ............................................................................................................................ 41 i 2.2 Results .............................................................................................................................................. 41 2.2.1 A Drastic Reduction of miR-185 Levels in Df(16)A +/– Mice ........................................................ 41 2.2.2 A Primary Transcriptional Consequence of 22q11.2 Genomic Losses ..................................... 43 2.2.3 2310044H10Rik as a Major Downstream Target of miRNAs Dysregulated in Df(16)A +/– Mice .......................................................................................................................... 45 2.3 Discussion ........................................................................................................................................ 51 2.3.1 CNV-associated miRNA Dysregulation ..................................................................................... 51 2.3.2 Convergent Downregulation of miRNAs in Schizophrenia Patients and Df(16)A +/– Mice .......... 53 2.3.3 Impact of Modest Dysregulation of miRNAs .............................................................................. 54 2.3.4 Not all miRNA Targets are Created Equal? ............................................................................... 55 2.4 Summary ........................................................................................................................................... 56 2.5 Methods ............................................................................................................................................ 63 2.6 References ........................................................................................................................................ 69 Chapter III − Dysregulation of A Novel Inhibitor of Dendritic and Spine Morphogenesis In Df(16)A +/– Mice ........................................................ 75 3.1 Introduction ...................................................................................................................................... 75 3.1.1 miRNA Regulation of Dendritic Arborization .............................................................................. 76 3.1.2 miRNA Regulation of Spine Morphogenesis ............................................................................. 77 3.1.3 Structural Alterations in Df(16)A +/– Neurons ............................................................................. 79 3.1.4 In this Chapter ............................................................................................................................ 80 3.2 Results .............................................................................................................................................. 81 3.2.1 Generation of Mirta22 Specific Antibody ................................................................................... 81 3.2.2 Mirta22 is a Neuronal Protein Residing in the Golgi Apparatus ................................................ 81 3.2.3 Coordinated Mild Dysregulation of Golgi-related Genes due to miR-185 Reduction ................ 85 3.2.4 Altered miR-185 Levels Contribute to Structural Alterations of Df(16)A +/− Neurons .................. 86 3.2.5 Elevation of Mirta22 Levels Inhibits Dendritic and Spine Development in Df(16)A +/– Neurons .................................................................................................................... 89 ii 3.3 Discussion ........................................................................................................................................ 92 3.3.1 What do We Know about Mirta22 Protein? ................................................................................ 92 3.3.2 A Neuronal Inhibitor
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