Doublecortin restricts neuronal branching by regulating tubulin polyglutamylation

Muriel Sébastien, Alexandra L. Paquette, Emily N. P. Prowse, Adam G. Hendricks and Gary J. Brouhard ()
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Muriel Sébastien: McGill University
Alexandra L. Paquette: McGill University
Emily N. P. Prowse: McGill University
Adam G. Hendricks: McGill University
Gary J. Brouhard: McGill University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56951-2

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