title: Dicer expression is essential for adult midbrain dopaminergic neuron maintenance and survival.
abstract: The type III RNAse, Dicer, is responsible for the processing of microRNA (miRNA) precursors into functional miRNA molecules, non-coding RNAs that bind to and target messenger RNAs for repression. Dicer expression is essential for mouse midbrain development and dopaminergic (DAergic) neuron maintenance and survival during the early post-natal period. However, the role of Dicer in adult mouse DAergic neuron maintenance and survival is unknown. To bridge this gap in knowledge, we selectively knocked-down Dicer expression in individual DAergic midbrain areas, including the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) via viral-mediated expression of Cre in adult floxed Dicer knock-in mice (Dicer(flox/flox)). Bilateral Dicer loss in the VTA resulted in progressive hyperactivity that was significantly reduced by the dopamine agonist, amphetamine. In contrast, decreased Dicer expression in the SNpc did not affect locomotor activity but did induce motor-learning impairment on an accelerating rotarod. Knock-down of Dicer in both midbrain regions of adult Dicer(flox/flox) mice resulted in preferential, progressive loss of DAergic neurons likely explaining motor behavior phenotypes. In addition, knock-down of Dicer in midbrain areas triggered neuronal death via apoptosis. Together, these data indicate that Dicer expression and, as a consequence, miRNA function, are essential for DAergic neuronal maintenance and survival in adult midbrain DAergic neuron brain areas.
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Pang
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Hogan
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Casserly
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01604, USA; Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Gardner
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604, USA. Electronic address: andrew.tapper@umassmed.edu.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tapper
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D007858:Learning; D008124:Locomotion; D008636:Mesencephalon / Q000166:cytology / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D009928:Organ Specificity; D010641:Phenotype; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*
chemical_list: D018491:Dopamine Agonists; D000661:Amphetamine; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: Dicer; Dopamine; MicroRNA; Midbrain; Neurodegeneration