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Upregulation of MicroRNA miR-9 Is Associated with Microcephaly and Zika Virus Infection in Mice

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Abstract

Proper growth of the mammalian cerebral cortex, which is determined by expansion and survival of neural progenitors and mature neurons, is crucial for cognitive functions. Here, we show a role of the dosage of microRNA miR-9 in controlling brain size. Cortical-specific upregulation of miR-9 causes microcephalic defects in mice, due to apoptosis, reduced neural progenitor pool, and decreased neurogenesis. Glial cell-derived neurotrophic factor (GDNF) is a target of miR-9, and protects neural progenitors from miR-9-induced apoptosis. Furthermore, Zika virus (ZIKV) infection in embryonic mouse cortex causes reduced numbers in neural progenitors and newborn neurons, and results in upregulation of miR-9, downregulation of its target GDNF. Our studies indicate an association of altered levels of miR-9 and its target GDNF with microcephaly and ZIKV infection in mice.

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Acknowledgements

We thank members of the Sun laboratory for their valuable discussions and advice. This work was supported by an award from the Hirschl/Weill-Caulier Trust (T. S.), an R01-MH083680 grant from the NIH/NIMH (T. S.) and the National Natural Science Foundation of China (81471152, 31771141 and 81701132).

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  1. Haijun Zhang, Yafei Chang, Longbin Zhang and Seung-Nam Kim contributed equally to this work.

Authors and Affiliations

  1. Department of Cell and Developmental Biology, Cornell University Weill Medical College, 1300 York Avenue, New York, NY, 10065, USA

    Haijun Zhang, Seung-Nam Kim, Gaizka Otaegi, Taufif Mubarak & Tao Sun

  2. School of Life Sciences and Technology, Shanghai Jiao Tong University, Shanghai, 200240, China

    Yafei Chang, Zhen Zhang & Yanzhen Nie

  3. Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen, 362021, China

    Longbin Zhang & Tao Sun

  4. Department of Korean Medicine, Dongguk University, 32 Donggukro, Ilsandonggu, Goyangsi, Gyeonggido, 10326, Republic of Korea

    Seung-Nam Kim

  5. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China

    Cui Li & Zhiheng Xu

  6. Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China

    Cheng-Feng Qin

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Contributions

G.O., Z.X., and T.S. designed the experiments. H.Z., Y.C., L.Z., S.K., G.O., Z.Z., T.M., and C.L. performed the experiments. H.Z., Y.C., L.Z., G.O., Z.Z, Y.N., C.Q., and T.S. analyzed and interpreted the data. T.S. wrote the manuscript and supervised the project.

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Correspondence to Tao Sun.

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Zhang, H., Chang, Y., Zhang, L. et al. Upregulation of MicroRNA miR-9 Is Associated with Microcephaly and Zika Virus Infection in Mice. Mol Neurobiol 56, 4072–4085 (2019). https://doi.org/10.1007/s12035-018-1358-4

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