Local application of neurotrophins specifies axons through inositol 1,4,5-trisphosphate, calcium, and Ca 2+/calmodulin-dependent protein kinases

Shinichi Nakamuta, Yasuhiro Funahashi, Takashi Namba, Nariko Arimura, Marina R. Picciotto, Hiroshi Tokumitsu, Thomas Soderling, Akira Sakakibara, Takaki Miyata, Hiroyuki Kamiguchi, Kozo Kaibuchi

    Research output: Contribution to journalArticle

    28 Citations (Scopus)

    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 (Ca 2+) in an inositol 1,4,5-trisphosphate (IP 3)-dependent fashion as well as local activation of the Ca 2+ effector Ca 2+/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 IP 3-Ca 2+-CaMKK signaling in axon specification.

    Original languageEnglish (US)
    JournalScience Signaling
    Volume4
    Issue number199
    DOIs
    StatePublished - Nov 15 2011

    Fingerprint

    Calcium-Calmodulin-Dependent Protein Kinases
    Inositol 1,4,5-Trisphosphate
    Nerve Growth Factors
    Axons
    Calcium
    Neurotrophin 3
    Neurites
    Neurons
    Specifications
    Phosphotransferases
    Brain-Derived Neurotrophic Factor
    Dendrites
    Nerve Growth Factor Receptors
    Growth Cones
    Cones
    Chemical activation
    Ions

    ASJC Scopus subject areas

    • Biochemistry
    • Cell Biology
    • Molecular Biology

    Cite this

    Local application of neurotrophins specifies axons through inositol 1,4,5-trisphosphate, calcium, and Ca 2+/calmodulin-dependent protein kinases. / Nakamuta, Shinichi; Funahashi, Yasuhiro; Namba, Takashi; Arimura, Nariko; Picciotto, Marina R.; Tokumitsu, Hiroshi; Soderling, Thomas; Sakakibara, Akira; Miyata, Takaki; Kamiguchi, Hiroyuki; Kaibuchi, Kozo.

    In: Science Signaling, Vol. 4, No. 199, 15.11.2011.

    Research output: Contribution to journalArticle

    Nakamuta, S, Funahashi, Y, Namba, T, Arimura, N, Picciotto, MR, Tokumitsu, H, Soderling, T, Sakakibara, A, Miyata, T, Kamiguchi, H & Kaibuchi, K 2011, 'Local application of neurotrophins specifies axons through inositol 1,4,5-trisphosphate, calcium, and Ca 2+/calmodulin-dependent protein kinases', Science Signaling, vol. 4, no. 199. https://doi.org/10.1126/scisignal.2002011
    Nakamuta, Shinichi ; Funahashi, Yasuhiro ; Namba, Takashi ; Arimura, Nariko ; Picciotto, Marina R. ; Tokumitsu, Hiroshi ; Soderling, Thomas ; Sakakibara, Akira ; Miyata, Takaki ; Kamiguchi, Hiroyuki ; Kaibuchi, Kozo. / Local application of neurotrophins specifies axons through inositol 1,4,5-trisphosphate, calcium, and Ca 2+/calmodulin-dependent protein kinases. In: Science Signaling. 2011 ; Vol. 4, No. 199.
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