Cdk5 regulation of the GRAB-mediated Rab8-Rab11 cascade in axon outgrowth

Kotaro Furusawa, Akiko Asada, Pamela Urrutia, Christian Gonzalez-Billault, Mitsunori Fukuda, Shin Ichi Hisanaga

    Research output: Contribution to journalArticle

    16 Citations (Scopus)

    Abstract

    Neurons communicate with each other through their axons and dendrites. However, a full characterization of the molecular mechanisms involved in axon and dendrite formation is still incomplete. Neurite outgrowth requires the supply of membrane components for surface expansion. Two membrane sources for axon outgrowth are suggested: Golgi secretary vesicles and endocytic recycling endosomes. In non-neuronal cells, trafficking of secretary vesicles from Golgi is regulated by Rab8, a member of Rab small GTPases, and that of recycling endosomes is by Rab11, another member of Rabs. However, whether these vesicles are coordinately or independently transported in growing axons is unknown. Herein, we find that GRAB, a guanine nucleotide exchange factor for Rab8, is a novel regulator of axon outgrowth. Knockdown of GRAB suppressed axon outgrowth of cultured mouse brain cortical neurons. GRAB mediates the interaction between Rab11A and Rab8A, and this activity is regulated by phosphorylation at Ser169 and Ser180 by Cdk5-p35. The nonphosphorylatable GRAB mutant S169/180A promoted axonal outgrowth to a greater extent than did the phosphomimetic GRAB mutant S169/180D. Phosphorylation of GRAB suppressed its guanine nucleotide exchange factor activity and its ability to recruit Rab8A-to Rab11A-positive endosomes. In vivo function of GRAB and its Cdk5-phophorylation were shown in migration and process formation of developing neurons in embryonic mouse brains. These results indicate that GRAB regulates axonal outgrowth via activation and recruitment of Rab8A-to Rab11A-positive endosomes in a Cdk5-dependent manner.

    Original languageEnglish
    Pages (from-to)790-806
    Number of pages17
    JournalJournal of Neuroscience
    Volume37
    Issue number4
    DOIs
    Publication statusPublished - 2017 Jan 25

    Keywords

    • Axon outgrowth
    • Cdk5
    • GRAB
    • Phosphorylation
    • Rab
    • Vesicle transport

    ASJC Scopus subject areas

    • Neuroscience(all)

    Fingerprint Dive into the research topics of 'Cdk5 regulation of the GRAB-mediated Rab8-Rab11 cascade in axon outgrowth'. Together they form a unique fingerprint.

  • Cite this

    Furusawa, K., Asada, A., Urrutia, P., Gonzalez-Billault, C., Fukuda, M., & Hisanaga, S. I. (2017). Cdk5 regulation of the GRAB-mediated Rab8-Rab11 cascade in axon outgrowth. Journal of Neuroscience, 37(4), 790-806. https://doi.org/10.1523/JNEUROSCI.2197-16.2016