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Sci. Signal., 15 November 2011
Vol. 4, Issue 199, p. ra76
[DOI: 10.1126/scisignal.2002011]

RESEARCH ARTICLES

Local Application of Neurotrophins Specifies Axons Through Inositol 1,4,5-Trisphosphate, Calcium, and Ca2+/Calmodulin–Dependent Protein Kinases

Shinichi Nakamuta1, Yasuhiro Funahashi1,2, Takashi Namba1,2, Nariko Arimura3, Marina R. Picciotto4, Hiroshi Tokumitsu5, Thomas R. Soderling6, Akira Sakakibara7, Takaki Miyata7, Hiroyuki Kamiguchi8, and Kozo Kaibuchi1,2*

1 Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan.
2 Japan Science and Technology Agency, CREST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
3 Frontal Lobe Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo 156-8506, Japan.
4 Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA.
5 Department of Signal Transduction Sciences, Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
6 Vollum Institute, Oregon Health and Sciences University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
7 Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan.
8 Laboratory for Neuronal Growth Mechanisms, Brain Science Institute, The Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.

Abstract: Neurons are highly polarized cells that have structurally distinct processes—the axons and dendrites—that differentiate from common immature neurites. In cultured hippocampal neurons, one of these immature neurites stochastically initiates rapid extension and becomes an axon, whereas the others become dendrites. Various extracellular and intracellular signals contribute to axon specification; however, the specific intracellular pathways whereby particular extracellular stimuli lead to axon specification remain to be delineated. Here, we found that the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) were required for axon specification in an autocrine or a paracrine fashion. Using local application with a micropipette to selectively stimulate individual neurites, we found that stimulation of a selected neurite by BDNF or NT-3 induced neurite outgrowth and subsequent axon formation. NT-3 induced a rapid increase in calcium ions (Ca2+) in an inositol 1,4,5-trisphosphate (IP3)–dependent fashion as well as local activation of the Ca2+ effector Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) in the growth cone. Inhibition of neurotrophin receptors or CaMKK attenuated NT-3–induced axon specification in cultured neurons and axon formation in cortical neurons in vivo. These results identify a role for IP3-Ca2+-CaMKK signaling in axon specification.

* To whom correspondence should be addressed. E-mail: kaibuchi{at}med.nagoya-u.ac.jp

Citation: S. Nakamuta, Y. Funahashi, T. Namba, N. Arimura, M. R. Picciotto, H. Tokumitsu, T. R. Soderling, A. Sakakibara, T. Miyata, H. Kamiguchi, K. Kaibuchi, Local Application of Neurotrophins Specifies Axons Through Inositol 1,4,5-Trisphosphate, Calcium, and Ca2+/Calmodulin–Dependent Protein Kinases. Sci. Signal. 4, ra76 (2011).

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