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Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system

Nature Neuroscience volume 12, pages 1506–1513 (2009)Cite this article

Abstract

Axonal maturation and myelination are essential processes for establishing an efficient neuronal signaling network. We found that nardilysin (N-arginine dibasic convertase, also known as Nrd1 and NRDc), a metalloendopeptidase enhancer of protein ectodomain shedding, is a critical regulator of these processes. Nrd1−/− mice had smaller brains and a thin cerebral cortex, in which there were less myelinated fibers with thinner myelin sheaths and smaller axon diameters. We also found hypomyelination in the peripheral nervous system (PNS) of Nrd1−/− mice. Neuron-specific overexpression of NRDc induced hypermyelination, indicating that the level of neuronal NRDc regulates myelin thickness. Consistent with these findings, Nrd1−/− mice had impaired motor activities and cognitive deficits. Furthermore, NRDc enhanced ectodomain shedding of neuregulin1 (NRG1), which is a master regulator of myelination in the PNS. On the basis of these data, we propose that NRDc regulates axonal maturation and myelination in the CNS and PNS, in part, through the modulation of NRG1 shedding.

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Figure 1: Expression of NRDc in brains and gross CNS phenotypes of Nrd1−/− mice.
Figure 2: Impaired axonal maturation and hypomyelination in the CNS of Nrd1−/− mice.
Figure 3: Delay in the initiation of myelination and hypomyelination in Nrd1−/− mice.
Figure 4: Impaired axonal maturation and hypomyelination in the PNS of Nrd1−/− mice.
Figure 5: Intermediate CNS phenotype in Nrd1+/− mice.
Figure 6: Transgenic overexpression of neuronal NRDc induces hypermyelination in the CNS.
Figure 7: Impaired motor activity and cognitive deficits in Nrd1−/− mice.
Figure 8: NRDc regulates NRG1 shedding through BACE1 and TACE.

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Acknowledgements

We are grateful to N. Nishimoto and H. Nakabayashi for technical assistance, and K. Matsumoto, E. Kimura, A. Kinoshita and A. Sehara for materials. We thank P.W. Park, T. Nishio, H. Fujiwara, T. Kaneko, F. Fujiyama and H. Kawasaki for critical reading of the manuscript. This study was supported by research grants (19041035, 20390255, 20659061, 20200068 and IBR-shien) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. It was also supported by the Takeda Science Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Suzuken Memorial Foundation, the Japan Health Foundation and the Daiichi Sankyo Sponsored Research Program.

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  1. Toru Kita

    Present address: Present address: Kobe City Medical Center General Hospital, Chuo-ku, Kobe, Japan.,

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan

    Mikiko Ohno, Yoshinori Hiraoka, Tatsuhiko Matsuoka, Takeshi Kimura, Toru Kita & Eiichiro Nishi

  2. Department of Neurology, Graduate School of Medicine, Mie University, Tsu, Japan

    Hidekazu Tomimoto

  3. Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan

    Keizo Takao & Tsuyoshi Miyakawa

  4. Japan Science and Technology Agency (JST), Institute for Bioinformatics Research and Development and Core Research for Evolutional Science and Technology, Kawaguchi, Saitama, Japan

    Keizo Takao & Tsuyoshi Miyakawa

  5. Frontier Technology Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan

    Keizo Takao & Tsuyoshi Miyakawa

  6. Laboratory for Animal Resources and Genetic Engineering, Center for Developmental Biology, RIKEN Kobe, Chuo-ku, Kobe, Japan

    Naoko Oshima & Hiroshi Kiyonari

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Contributions

M.O. and E.N. planned the experiments and wrote the manuscript. M.O., Y.H., T.M. and E.N. performed the experiments. H.T. carried out the histological procedures. K.T. and T.M. performed behavioral analysis. N.O. and H.K. generated the Nrd1−/− mice. T. Kimura and T. Kita supervised the work.

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Correspondence to Eiichiro Nishi.

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Ohno, M., Hiraoka, Y., Matsuoka, T. et al. Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system. Nat Neurosci 12, 1506–1513 (2009). https://doi.org/10.1038/nn.2438

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