Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons

Yoshiaki V. Nishimura, Mima Shikanai, Mikio Hoshino, Toshio Ohshima, Yo Ichi Nabeshima, Ken Ichi Mizutani, Koh Ichi Nagata, Kazunori Nakajima, Takeshi Kawauchi

    Research output: Contribution to journalArticle

    25 Citations (Scopus)

    Abstract

    Neuronalmigration is crucial fordevelopment of themammalian-specific six-layered cerebral cortex. Migrating neurons are known to exhibit distinct features; they form a cytoplasmic dilation, a structure specific to migrating neurons, at the proximal region of the leading process, followed by nuclear elongation and forward movement. However, the molecular mechanisms of dilation formation and nuclear elongation remain unclear. Using ex vivo chemical inhibitor experiments, we show here that rottlerin, which is widely used as a specific inhibitor for PKCδ, suppresses the formation of a cytoplasmic dilation and nuclear elongation in cortical migrating neurons. Although our previous study showed that cortical neuronal migration depends on Jnk, another downstream target of rottlerin, Jnk inhibition disturbs only the nuclear elongation and forward movement, but not the dilation formation. We found that an unconventional cyclin-dependent kinase, Cdk5, is a novel downstream target of rottlerin, and that pharmacological or knockdown-mediated inhibition of Cdk5 suppresses both the dilation formation and nuclear elongation. We also show that Cdk5 inhibition perturbs endocytic trafficking as well as microtubule organization, both of which have been shown to be required for dilation formation. Furthermore, knockdown of Dcx, a Cdk5 substrate involved in microtubule organization and membrane trafficking, or p27kip1, another Cdk5 substrate involved in actin and microtubule organization, disturbs the dilation formation and nuclear elongation. These data suggest that Cdk5 and its substrates,Dcx and p27kip1, characterizemigratingneuronspecific features, cytoplasmic dilation formation and nuclear elongation in the mouse cerebral cortex, possibly through the regulation of microtubule organization and an endocytic pathway.

    Original languageEnglish
    Pages (from-to)3540-3550
    Number of pages11
    JournalDevelopment (Cambridge)
    Volume141
    Issue number18
    DOIs
    Publication statusPublished - 2014

    Fingerprint

    Dilatation
    Neurons
    Microtubules
    Cerebral Cortex
    Cyclin-Dependent Kinases
    Actins
    Pharmacology
    Membranes
    rottlerin

    Keywords

    • C-jun N-terminal kinase
    • Cdkn1b
    • Cell migration
    • Cytoskeleton
    • Doublecortin
    • Endocytosis
    • Mouse
    • Rab5

    ASJC Scopus subject areas

    • Developmental Biology
    • Molecular Biology

    Cite this

    Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons. / Nishimura, Yoshiaki V.; Shikanai, Mima; Hoshino, Mikio; Ohshima, Toshio; Nabeshima, Yo Ichi; Mizutani, Ken Ichi; Nagata, Koh Ichi; Nakajima, Kazunori; Kawauchi, Takeshi.

    In: Development (Cambridge), Vol. 141, No. 18, 2014, p. 3540-3550.

    Research output: Contribution to journalArticle

    Nishimura, YV, Shikanai, M, Hoshino, M, Ohshima, T, Nabeshima, YI, Mizutani, KI, Nagata, KI, Nakajima, K & Kawauchi, T 2014, 'Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons', Development (Cambridge), vol. 141, no. 18, pp. 3540-3550. https://doi.org/10.1242/dev.111294
    Nishimura, Yoshiaki V. ; Shikanai, Mima ; Hoshino, Mikio ; Ohshima, Toshio ; Nabeshima, Yo Ichi ; Mizutani, Ken Ichi ; Nagata, Koh Ichi ; Nakajima, Kazunori ; Kawauchi, Takeshi. / Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons. In: Development (Cambridge). 2014 ; Vol. 141, No. 18. pp. 3540-3550.
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