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Mitotic impairment by doublecortin is diminished by doublecortin mutations found in patients

Sebastien Couillard-Despres1, Goekhan Uyanik, Sonja Ploetz

  • 1Department of Neurology, University of Regensburg, Franz Josef Strauss Allee 11, 93053 Regensburg, Germany.

Neurogenetics
|March 27, 2004
PubMed

Insights

Mutations in doublecortin (DCX) impact neuronal migration, causing brain malformations. Mutant DCX shows reduced ability to affect cell division, correlating with clinical severity, offering a new diagnostic tool for these disorders.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Mutations in the doublecortin (DCX) gene are linked to neuronal migration disorders like subcortical band heterotopia and lissencephaly.
  • DCX protein's role in microtubule binding and bundling is established, but the functional consequences of mutations on cellular processes remain incompletely understood.

Purpose of the Study:

  • To investigate the impact of DCX mutations on microtubule networks and cellular functions related to neuronal migration.
  • To establish a cell-based assay for predicting the clinical severity of DCX-associated disorders.

Main Methods:

  • Analysis of wild-type and mutant DCX proteins in COS7 cell microtubule networks.
  • Assessment of the effects of DCX variants on mitotic machinery, spindle orientation, and mitotic progression.

Main Results:

  • Both wild-type and mutant DCX bind and bundle microtubules.
  • Mutant DCX exhibited a diminished capacity to perturb the mitotic machinery, induce abnormal spindle orientation, and impair mitotic progression compared to wild-type.
  • The degree of functional impairment in mutants was proportional to the clinical severity of associated disorders.

Conclusions:

  • DCX mutations impair its ability to modulate microtubule dynamics during mitosis, contributing to neuronal migration defects.
  • The observed correlation between functional impairment and clinical severity provides a basis for a cell-based prognostic assay for DCX-related neuronal migration disorders.

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