Mitotic impairment by doublecortin is diminished by doublecortin mutations found in patients.
Mutations in doublecortin ( DCX) affect the migration of neuronal precursor cells and cause subcortical band heterotopia and lissencephaly. DCX is known to bind and bundle microtubules; however, the impact of mutation on DCX function and its relation to the manifestation of DCX-associated disorders is still unclear. We analyzed the impact of DCX mutants on COS7 cell microtubule networks. We found that both mutant and wild type DCX are able to bind and bundle microtubules; however, mutants possess a decreased ability to perturb the mitotic machinery, to cause abnormal spindle orientation, and to impair mitotic progression. The magnitude of this decrease is proportional to the severity of the mutation-associated clinical symptoms, thereby providing a cell-based assay for the prognosis of DCX-associated neuronal migration disorders.
Couillard-Despres
Sebastien
S
Department of Neurology, University of Regensburg, Franz Josef Strauss Allee 11, 93053 Regensburg, Germany.
Uyanik
Goekhan
G
Ploetz
Sonja
S
Karl
Claudia
C
Koch
Hartmut
H
Winkler
Juergen
J
Aigner
Ludwig
L
D000818:Animals; D019556:COS Cells; D002465:Cell Movement; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000473:pathology*; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype
C000714328:DCX protein, human; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides