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Updated: May 27, 2025

Genetic Manipulation of Cerebellar Granule Neurons In Vitro and In Vivo to Study Neuronal Morphology and Migration
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Doublecortin restricts neuronal branching by regulating tubulin polyglutamylation

Muriel Sébastien1,2, Alexandra L Paquette1, Emily N P Prowse2

  • 1Department of Biology, McGill University, Montréal, QC, Canada.

Nature Communications
|February 18, 2025
PubMed

Insights

Doublecortin (DCX) regulates neuronal development. This study reveals DCX positively controls alpha-tubulin polyglutamylation, impacting neurite branching and neuronal migration.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Doublecortin (DCX) is crucial for neuronal migration and microtubule structure.
  • Mutations in DCX lead to brain malformations like lissencephaly.
  • The precise role of DCX in regulating the tubulin code is not fully understood.

Purpose of the Study:

  • To investigate the role of Doublecortin in regulating microtubule modifications and neuronal development.
  • To elucidate the mechanism by which DCX influences neurite branching and neuronal migration.
  • To explore the relationship between DCX, alpha-tubulin polyglutamylation, and the tubulin code.

Main Methods:

  • CRISPR/Cas9 gene editing to create Doublecortin knockout (DCX-KO) induced pluripotent stem cells.
  • Differentiation of DCX-KO cells into cortical neurons for functional analysis.
  • Assessment of nuclear movement velocities, neurite outgrowth, and alpha-tubulin polyglutamylation levels.
  • Rescue experiments using Doublecortin or TTLL11 expression.

Main Results:

  • DCX-KO neurons exhibited reduced nuclear movement velocities and increased early neurite formation.
  • Alpha-tubulin polyglutamylation was significantly reduced in DCX-KO neurons.
  • Neurite branching and polyglutamylation defects were rescued by expressing DCX or TTLL11.
  • DCX and TTLL11 demonstrated synergistic effects on polyglutamylation in an orthogonal cell system.

Conclusions:

  • Doublecortin acts as a positive regulator of alpha-tubulin polyglutamylation.
  • DCX influences neuronal development by modulating the tubulin code, restricting excessive neurite branching.
  • These findings reveal a novel function for Doublecortin in maintaining tubulin homeostasis during neuronal development.

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