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Septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation

Author

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  • Natsumi Ageta-Ishihara

    (Nagoya University Graduate School of Science)

  • Takaki Miyata

    (Nagoya University Graduate School of Medicine)

  • Chika Ohshima

    (Nagoya University Graduate School of Science)

  • Masahiko Watanabe

    (Hokkaido University Graduate School of Medicine)

  • Yoshikatsu Sato

    (Institute of Transformative Bio-Molecules, Nagoya University)

  • Yuki Hamamura

    (Nagoya University Graduate School of Science)

  • Tetsuya Higashiyama

    (Institute of Transformative Bio-Molecules, Nagoya University)

  • Ralph Mazitschek

    (Centre for Systems Biology, Massachusetts General Hospital and Harvard Medical School)

  • Haruhiko Bito

    (Graduate School of Medicine, The University of Tokyo)

  • Makoto Kinoshita

    (Nagoya University Graduate School of Science)

Abstract

Neurite growth requires two guanine nucleotide-binding protein polymers of tubulins and septins. However, whether and how those cytoskeletal systems are coordinated was unknown. Here we show that the acute knockdown or knockout of the pivotal septin subunit SEPT7 from cerebrocortical neurons impairs their interhemispheric and cerebrospinal axon projections and dendritogenesis in perinatal mice, when the microtubules are severely hyperacetylated. The resulting hyperstabilization and growth retardation of microtubules are demonstrated in vitro. The phenotypic similarity between SEPT7 depletion and the pharmacological inhibition of α-tubulin deacetylase HDAC6 reveals that HDAC6 requires SEPT7 not for its enzymatic activity, but to associate with acetylated α-tubulin. These and other findings indicate that septins provide a physical scaffold for HDAC6 to achieve efficient microtubule deacetylation, thereby negatively regulating microtubule stability to an optimal level for neuritogenesis. Our findings shed light on the mechanisms underlying the HDAC6-mediated coupling of the two ubiquitous cytoskeletal systems during neural development.

Suggested Citation

  • Natsumi Ageta-Ishihara & Takaki Miyata & Chika Ohshima & Masahiko Watanabe & Yoshikatsu Sato & Yuki Hamamura & Tetsuya Higashiyama & Ralph Mazitschek & Haruhiko Bito & Makoto Kinoshita, 2013. "Septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3532
    DOI: 10.1038/ncomms3532
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    Cited by:

    1. Sabrina Villar-Pazos & Laurel Thomas & Yunhan Yang & Kun Chen & Jenea B. Lyles & Bradley J. Deitch & Joseph Ochaba & Karen Ling & Berit Powers & Sebastien Gingras & Holly B. Kordasiewicz & Melanie J. , 2023. "Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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