Discovery of long-range inhibitory signaling to ensure single axon formation

Tetsuya Takano, Mengya Wu, Shinichi Nakamuta, Honda Naoki, Naruki Ishizawa, Takashi Namba, Takashi Watanabe, Chundi Xu, Tomonari Hamaguchi, Yoshimitsu Yura, Mutsuki Amano, Klaus M. Hahn and Kozo Kaibuchi ()
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Tetsuya Takano: Nagoya University Graduate School of Medicine
Mengya Wu: Nagoya University Graduate School of Medicine
Shinichi Nakamuta: Nagoya University Graduate School of Medicine
Honda Naoki: Kyoto University
Naruki Ishizawa: Nagoya University Graduate School of Medicine
Takashi Namba: Nagoya University Graduate School of Medicine
Takashi Watanabe: University of North Carolina
Chundi Xu: Nagoya University Graduate School of Medicine
Tomonari Hamaguchi: Nagoya University Graduate School of Medicine
Yoshimitsu Yura: Nagoya University Graduate School of Medicine
Mutsuki Amano: Nagoya University Graduate School of Medicine
Klaus M. Hahn: University of North Carolina
Kozo Kaibuchi: Nagoya University Graduate School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: Abstract A long-standing question in neurodevelopment is how neurons develop a single axon and multiple dendrites from common immature neurites. Long-range inhibitory signaling from the growing axon is hypothesized to prevent outgrowth of other immature neurites and to differentiate them into dendrites, but the existence and nature of this inhibitory signaling remains unknown. Here, we demonstrate that axonal growth triggered by neurotrophin-3 remotely inhibits neurite outgrowth through long-range Ca2+ waves, which are delivered from the growing axon to the cell body. These Ca2+ waves increase RhoA activity in the cell body through calcium/calmodulin-dependent protein kinase I. Optogenetic control of Rho-kinase combined with computational modeling reveals that active Rho-kinase diffuses to growing other immature neurites and inhibits their outgrowth. Mechanistically, calmodulin-dependent protein kinase I phosphorylates a RhoA-specific GEF, GEF-H1, whose phosphorylation enhances its GEF activity. Thus, our results reveal that long-range inhibitory signaling mediated by Ca2+ wave is responsible for neuronal polarization.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00044-2

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DOI: 10.1038/s41467-017-00044-2

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