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Cell Death Differ. 2018 Dec 18. doi: 10.1038/s41418-018-0257-6. [Epub ahead of print]

MicroRNA-197 controls ADAM10 expression to mediate MeCP2's role in the differentiation of neuronal progenitors.

Wang YM1,2, Zheng YF3,4,5, Yang SY1,2, Yang ZM6, Zhang LN7, He YQ6, Gong XH2, Liu D8, Finnell RH9,10, Qiu ZL11, Du YS12, Wang HY13,14,15,16.

Author information

1
Institute of Developmental Biology & Molecular Medicine, School of Life Sciences, Fudan University, 200433, Shanghai, China.
2
Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, 200011, Shanghai, China.
3
Institute of Developmental Biology & Molecular Medicine, School of Life Sciences, Fudan University, 200433, Shanghai, China. zhengyf@fudan.edu.cn.
4
Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, 200011, Shanghai, China. zhengyf@fudan.edu.cn.
5
Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center of Genetics and Development, Fudan University, 200032, Shanghai, China. zhengyf@fudan.edu.cn.
6
Department of Biochemistry and Molecular Biology, College of life Sciences, Shaanxi Normal University, 710062, Xi'an, China.
7
Shanghai Mental Health Center, Shanghai Jiaotong University, 200030, Shanghai, China.
8
Co-innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 226001, Nantong, Jiangsu, China.
9
Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
10
Collaborative Innovation Center for Genetics & Development, School of Life Sciences, Fudan University, 200438, Shanghai, China.
11
Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
12
Shanghai Mental Health Center, Shanghai Jiaotong University, 200030, Shanghai, China. 13501942224@163.com.
13
Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, 200011, Shanghai, China. wanghy@fudan.edu.cn.
14
Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center of Genetics and Development, Fudan University, 200032, Shanghai, China. wanghy@fudan.edu.cn.
15
Children's Hospital of Fudan University, 399 Wanyuan Road, 201102, Shanghai, China. wanghy@fudan.edu.cn.
16
Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, China. wanghy@fudan.edu.cn.

Abstract

Duplication of MECP2 (Methyl-CpG-binding protein 2) causes severe mental illness called MECP2 duplication syndrome (MDS), yet the underlying mechanism remains elusive. Here we show, in Tg(MECP2) transgenic mouse brain or cultured neural progenitor cells (NPCs), that elevated MeCP2 expression promotes NPC differentiation into neurons. Ectopic expression of MeCP2 inhibits ADAM10 and thus the NOTCH pathway during NPC differentiation. In human cells, this downregulation on ADAM10 was mediated by miRNA-197, which is upregulated by MeCP2. Surprisingly, miR-197 binds to the ADAM10 3'-UTR via its 3' side, not the canonical seed sequence on the 5' side. In mouse cells, a noncoding RNA Gm28836 is used to replace the function of miR-197 between MeCP2 and ADAM10. Similar to MeCP2, overexpressing miR-197 also promotes NPCs differentiation into neurons. Interestingly, three rare missense mutations (H371R, E394K, and G428S) in MECP2, which we identified in a Han Chinese autism spectrum disorders (ASD) cohort showed loss-of-function effects in NPC differentiation assay. These mutations cannot upregulate miR-197. Overexpressing miR-197 together with these MeCP2 mutations could rescue the downregulation on ADAM10. Not only the inhibitor of miR-197 could reverse the effect of overexpressed MeCP2 on NPCs differentiation, but also overexpression of miR-197 could reverse the NPCs differentiation defects caused by MECP2 mutations. Our results revealed that a regulatory axis involving MeCP2, miR-197, ADAM10, and NOTCH signaling is critical for NPC differentiation, which is affected by both MeCP2 duplication and mutation.

PMID:
30560934
DOI:
10.1038/s41418-018-0257-6

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