Dicer expression is essential for adult midbrain dopaminergic neuron maintenance and survival
Brudnick Neuropsychiatric Research Institute, Department of Psychiatry; Gene Therapy Center; Department of Microbiology and Physiological Systems; Tapper Lab
Developmental Neuroscience | Molecular and Cellular Neuroscience
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.
DOI of Published Version
Mol Cell Neurosci. 2014 Jan;58:22-8. doi: 10.1016/j.mcn.2013.10.009. Epub 2013 Oct 31. Link to article on publisher's site
Molecular and cellular neurosciences
Pang X, Hogan EM, Casserly A, Gao G, Gardner PD, Tapper AR. (2014). Dicer expression is essential for adult midbrain dopaminergic neuron maintenance and survival. Morningside Graduate School of Biomedical Sciences Student Publications. https://doi.org/10.1016/j.mcn.2013.10.009. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1990