Cyclic nucleotide control of microtubule dynamics for axon guidance

Hiroki Akiyama, Tetsuko Fukuda, Takuro Tojima, Viacheslav O. Nikolaev, Hiroyuki Kamiguchi*

*この研究の対応する著者

    研究成果: Article査読

    28 被引用数 (Scopus)

    抄録

    Graded distribution of intracellular second messengers, such as Ca2+ and cyclic nucleotides, mediates directional cell migration, including axon navigational responses to extracellular guidance cues, in the developing nervous system. Elevated concentrations of cAMP or cGMP on one side of the neuronal growth cone induce its attractive or repulsive turning, respectively. Although effector processes downstream of Ca2+ have been extensively studied, very little is known about the mechanisms that enable cyclic nucleotides to steer migrating cells. Here, we show that asymmetric cyclic nucleotide signaling across the growth cone mediates axon guidance via modulating microtubule dynamics and membrane organelle transport. In embryonic chick dorsal root ganglion neurons in culture, contact of an extending microtubule with the growth cone leading edge induces localized membrane protrusion at the site of microtubule contact. Such a contact-induced protrusion requires exocytosis of vesicle-associated membrane protein 7 (VAMP7)-positive vesicles that have been transported centrifugally along the microtubule. We found that the two cyclic nucleotides counteractively regulate the frequency of microtubule contacts and targeted delivery of VAMP7 vesicles: cAMP stimulates and cGMP inhibits these events, thereby steering the growth cone in the opposite directions. By contrast, Ca2+ signals elicit no detectable change in either microtubule contacts or VAMP7 vesicle delivery during Ca2+-induced growth cone turning. Our findings clearly demonstrate growth cone steering machinery downstream of cyclic nucleotide signaling and highlight a crucial role of dynamic microtubules in leading-edge protrusion for cell chemotaxis.

    本文言語English
    ページ(範囲)5636-5649
    ページ数14
    ジャーナルJournal of Neuroscience
    36
    20
    DOI
    出版ステータスPublished - 2016 5月 18

    ASJC Scopus subject areas

    • 神経科学(全般)

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