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Doublecortin restricts neuronal branching by regulating tubulin polyglutamylation

Author

Listed:
  • Muriel Sébastien

    (McGill University
    McGill University)

  • Alexandra L. Paquette

    (McGill University)

  • Emily N. P. Prowse

    (McGill University)

  • Adam G. Hendricks

    (McGill University)

  • Gary J. Brouhard

    (McGill University)

Abstract

Doublecortin is a neuronal microtubule-associated protein that regulates microtubule structure in neurons. Mutations in Doublecortin cause lissencephaly and subcortical band heterotopia by impairing neuronal migration. We use CRISPR/Cas9 to knock-out the Doublecortin gene in induced pluripotent stem cells and differentiate the cells into cortical neurons. DCX-KO neurons show reduced velocities of nuclear movements and an increased number of neurites early in neuronal development, consistent with previous findings. Neurite branching is regulated by a host of microtubule-associated proteins, as well as by microtubule polymerization dynamics. However, EB comet dynamics are unchanged in DCX-KO neurons. Rather, we observe a significant reduction in α-tubulin polyglutamylation in DCX-KO neurons. Polyglutamylation levels and neuronal branching are rescued by expression of Doublecortin or of TTLL11, an α-tubulin glutamylase. Using U2OS cells as an orthogonal model system, we show that DCX and TTLL11 act synergistically to promote polyglutamylation. We propose that Doublecortin acts as a positive regulator of α-tubulin polyglutamylation and restricts neurite branching. Our results indicate an unexpected role for Doublecortin in the homeostasis of the tubulin code.

Suggested Citation

  • Muriel Sébastien & Alexandra L. Paquette & Emily N. P. Prowse & Adam G. Hendricks & Gary J. Brouhard, 2025. "Doublecortin restricts neuronal branching by regulating tubulin polyglutamylation," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56951-2
    DOI: 10.1038/s41467-025-56951-2
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    References listed on IDEAS

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    1. Brigette Y. Monroy & Danielle L. Sawyer & Bryce E. Ackermann & Melissa M. Borden & Tracy C. Tan & Kassandra M. Ori-McKenney, 2018. "Competition between microtubule-associated proteins directs motor transport," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
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