Abstract
Neocortical development is an extremely complicated process that critically depends on the proper migration, distribution, and positioning of neural cells. Here, we identified mitochondria-localized glutamic acid-rich protein (MGARP) as a negative regulator of neocortical development. In the developing neocortex, the overexpression of MGARP by in utero electroporation impedes the radial migration of neocortical cells to their final destination. These neocortical cells failed to be normally polarized, leading to shortened axons and compromised axonal bundles. The number of dendrites was also attenuated in cells with MGARP overexpression and was expanded in MGARP-knockdown or knockout cells. Mechanistic studies indicated that overexpression of MGARP caused alterations in the structural integrity, subcellular distribution, and motility of mitochondria. The mitochondria in MGARP-overexpressing cells became “fatty” with a round morphology, and the total number of mitochondria in MGARP-overexpressing cells was also decreased in the cell body and dendrites as well as in the axons. Time lapse studies showed that the ratio of motile mitochondria was remarkably decreased in the axons of MGARP-overexpressing cells. Together, our findings suggest that MGARP negatively mediates neocortical development by regulating mitochondrial distribution and motility in neocortical neurons.
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Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (No. 81171063) and the Ministry of Agriculture of China (2011ZX08009). We sincerely thank Prof. Guo-li Ming (Department of Neurology, Johns Hopkins University School of Medicine, USA) for constructive suggestions and reviewing our manuscript. We also appreciate the hard work of Prof. Shaoyong Chen (Beth Israel Deaconess Medical Center, Harvard Medical School, USA) for reading our manuscript and Prof. Xiaobing Yuan for technical instruction. We are grateful to all the professors who kindly provided us the constructs and Dr. Lei Huang (Center for Biomedical Analysis, Tsinghua University) for some help with the calculation.
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Liyun Jia and Tong Liang contributed equally to this work.
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Supplementary video 1
Dynamics of mitochondria in the control vector-transfected axon (AVI 15621 kb)
Supplementary video 2
Dynamics of mitochondria in the MGARP-overexpression vector-transfected axon (AVI 15621 kb)
Supplementary video 3
Dynamics of mitochondria in the control vector-transfected cell body (AVI 15621 kb)
Supplementary video 4
Dynamics of mitochondria in the MGARP-overexpression vector-transfected cell body (AVI 15621 kb)
Supplementary video 5
Dynamics of mitochondria in the scramble vector-transfected axon (AVI 15621 kb)
Supplementary video 6
Dynamics of mitochondria in the MGARP shRNA vector-transfected axon (AVI 15621 kb)
Supplementary video 7
Dynamics of mitochondria in the scramble vector-transfected cell body (AVI 15621 kb)
Supplementary video 8
Dynamics of mitochondria in the MGARP shRNA vector-transfected cell body (AVI 15621 kb)
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Jia, L., Liang, T., Yu, X. et al. MGARP Regulates Mouse Neocortical Development via Mitochondrial Positioning. Mol Neurobiol 49, 1293–1308 (2014). https://doi.org/10.1007/s12035-013-8602-8
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DOI: https://doi.org/10.1007/s12035-013-8602-8