title: Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder.
abstract: Bipolar disorder (BD) is a heritable neuropsychiatric disorder with largely unknown pathogenesis. Given their prominent role in brain function and disease, we hypothesized that microRNAs (miRNAs) might be of importance for BD. Here we show that levels of miR-34a, which is predicted to target multiple genes implicated as genetic risk factors for BD, are increased in postmortem cerebellar tissue from BD patients, as well as in BD patient-derived neuronal cultures generated by reprogramming of human fibroblasts into induced neurons or into induced pluripotent stem cells (iPSCs) subsequently differentiated into neurons. Of the predicted miR-34a targets, we validated the BD risk genes ankyrin-3 (ANK3) and voltage-dependent L-type calcium channel subunit beta-3 (CACNB3) as direct miR-34a targets. Using human iPSC-derived neuronal progenitor cells, we further show that enhancement of miR-34a expression impairs neuronal differentiation, expression of synaptic proteins and neuronal morphology, whereas reducing endogenous miR-34a expression enhances dendritic elaboration. Taken together, we propose that miR-34a serves as a critical link between multiple etiological factors for BD and its pathogenesis through the regulation of a molecular network essential for neuronal development and synaptogenesis.
authors.affiliation: 1] Chemical Neurobiology Laboratory, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bavamian
authors.affiliation: Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Mellios
authors.affiliation: 1] Chemical Neurobiology Laboratory, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [3] Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: J
authors.identifier: 0000000267971894
authors.initials: J
authors.lastname: Lalonde
authors.affiliation: 1] Chemical Neurobiology Laboratory, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Fass
authors.affiliation: 1] Chemical Neurobiology Laboratory, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [3] Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA [4] Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1] Chemical Neurobiology Laboratory, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [3] Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA [4] Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA [5] Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Sheridan
authors.affiliation: 1] Chemical Neurobiology Laboratory, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [3] Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Madison
authors.affiliation: 1] Chemical Neurobiology Laboratory, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [3] Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Zhou
authors.affiliation: 1] Chemical Neurobiology Laboratory, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [3] Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: E H
authors.initials: EH
authors.lastname: Rueckert
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Barker
authors.affiliation: 1] Chemical Neurobiology Laboratory, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [3] Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA [4] Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Perlis
authors.affiliation: Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sur
authors.affiliation: 1] Chemical Neurobiology Laboratory, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [3] Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA [4] Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA [5] Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Haggarty
mesh_terms: D000293:Adolescent; D000328:Adult; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism; D001714:Bipolar Disorder / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009716:Numerical Analysis, Computer-Assisted; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C490613:ANK3 protein, human; D017487:Ankyrins; C096073:CACNB3 protein, human; D015220:Calcium Channels; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D014157:Transcription Factors