Genetic interactions between doublecortin and doublecortin-like kinase in neuronal migration and axon outgrowth.
Although mutations in the human doublecortin gene (DCX) cause profound defects in cortical neuronal migration, a genetic deletion of Dcx in mice produces a milder defect. A second locus, doublecortin-like kinase (Dclk), encodes a protein with similar "doublecortin domains" and microtubule stabilization properties that may compensate for Dcx. Here, we generate a mouse with a Dclk mutation that causes no obvious migrational abnormalities but show that mice mutant for both Dcx and Dclk demonstrate perinatal lethality, disorganized neocortical layering, and profound hippocampal cytoarchitectural disorganization. Surprisingly, Dcx(-/y);Dclk(-/-) mutants have widespread axonal defects, affecting the corpus callosum, anterior commissure, subcortical fiber tracts, and internal capsule. Dcx/Dclk-deficient dissociated neurons show abnormal axon outgrowth and dendritic structure, with defects in axonal transport of synaptic vesicle proteins. Dcx and Dclk may directly or indirectly regulate microtubule-based vesicle transport, a process critical to both neuronal migration and axon outgrowth.
Deuel
Thomas A S
TA
Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Liu
Judy S
JS
Corbo
Joseph C
JC
Yoo
Seung-Yun
SY
Rorke-Adams
Lucy B
LB
Walsh
Christopher A
CA
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D001921:Brain / Q000002:abnormalities / Q000196:embryology; D002465:Cell Movement / Q000502:physiology*; D000013:Congenital Abnormalities / Q000235:genetics / Q000401:mortality / Q000473:pathology; D003712:Dendrites / Q000648:ultrastructure; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D000089742:Doublecortin-Like Kinases; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000502:physiology; D019579:Neocortex / Q000196:embryology; D009419:Nerve Tissue Proteins / Q000172:deficiency; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism; D014022:Tissue Survival
C000714328:DCX protein, human; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases