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Nat Neurosci. 2018 Dec;21(12):1689-1703. doi: 10.1038/s41593-018-0261-7. Epub 2018 Nov 5.

Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a.

Cheng Y1, Wang ZM2,3, Tan W3,4, Wang X3,4, Li Y1, Bai B5, Li Y5, Zhang SF2,3, Yan HL2,3, Chen ZL2,3, Liu CM2,3,6, Mi TW2,3, Xia S7, Zhou Z7, Liu A7, Tang GB2,3, Liu C2,3, Dai ZJ2,3, Wang YY2,3, Wang H5, Wang X5, Kang Y1, Lin L1, Chen Z3,4, Xie N1, Sun Q3,4, Xie W7, Peng J5, Chen D8,9, Teng ZQ10,11, Jin P12.

Author information

1
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
2
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, P. R. China.
3
University of Chinese Academy of Sciences, Beijing, P. R. China.
4
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, P. R. China.
5
Departments of Structural Biology and Developmental Neurobiology, Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, USA.
6
Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, P. R. China.
7
The Key Laboratory of Developmental Genes and Human Disease, Institute for Brain and Intelligence, Southeast University, Nanjing, P. R. China.
8
University of Chinese Academy of Sciences, Beijing, P. R. China. chendh@ioz.ac.cn.
9
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, P. R. China. chendh@ioz.ac.cn.
10
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, P. R. China. tengzq@ioz.ac.cn.
11
University of Chinese Academy of Sciences, Beijing, P. R. China. tengzq@ioz.ac.cn.
12
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA. peng.jin@emory.edu.

Abstract

Genetic analyses have linked microRNA-137 (MIR137) to neuropsychiatric disorders, including schizophrenia and autism spectrum disorder. miR-137 plays important roles in neurogenesis and neuronal maturation, but the impact of miR-137 loss-of-function in vivo remains unclear. Here we show the complete loss of miR-137 in the mouse germline knockout or nervous system knockout (cKO) leads to postnatal lethality, while heterozygous germline knockout and cKO mice remain viable. Partial loss of miR-137 in heterozygous cKO mice results in dysregulated synaptic plasticity, repetitive behavior, and impaired learning and social behavior. Transcriptomic and proteomic analyses revealed that the miR-137 mRNA target, phosphodiesterase 10a (Pde10a), is elevated in heterozygous knockout mice. Treatment with the Pde10a inhibitor papaverine or knockdown of Pde10a ameliorates the deficits observed in the heterozygous cKO mice. Collectively, our results suggest that MIR137 plays essential roles in postnatal neurodevelopment and that dysregulation of miR-137 potentially contributes to neuropsychiatric disorders in humans.

PMID:
30397325
PMCID:
PMC6261680
DOI:
10.1038/s41593-018-0261-7
[Indexed for MEDLINE]
Free PMC Article

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