TY - JOUR
T1 - Discovery of long-range inhibitory signaling to ensure single axon formation
AU - Takano, Tetsuya
AU - Wu, Mengya
AU - Nakamuta, Shinichi
AU - Naoki, Honda
AU - Ishizawa, Naruki
AU - Namba, Takashi
AU - Watanabe, Takashi
AU - Xu, Chundi
AU - Hamaguchi, Tomonari
AU - Yura, Yoshimitsu
AU - Amano, Mutsuki
AU - Hahn, Klaus M.
AU - Kaibuchi, Kozo
N1 - Publisher Copyright:
© 2017 The Author(s).
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-00044-2
DO - 10.1038/s41467-017-00044-2
M3 - Article
C2 - 28652571
AN - SCOPUS:85021669701
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 33
ER -