TY - JOUR
T1 - Genetic interactions between doublecortin and doublecortin-like kinase in neuronal migration and axon outgrowth
AU - Deuel, Thomas A.S.
AU - Liu, Judy S.
AU - Corbo, Joseph C.
AU - Yoo, Seung Yun
AU - Rorke-Adams, Lucy B.
AU - Walsh, Christopher A.
N1 - Funding Information:
We would like to thank members of the Walsh Lab for their help and Seonhee Kim for advice during all stages of this work. The pCAG-GFP vector was provided by T. Matsuda and C. Cepko (Harvard Medical School). The C-terminal antibody for Dclk was provided by O. Reiner (Weizman Institute, Israel), and the N-terminal antibody was provided by M. Mizuguchi and S. Takashima (Jichi Medical School, Japan). Dcx RNAi and control RNAi constructs were provided by J. LoTurco (University of Connecticut). G10 antibody was provided by A. Goffinet (University of Louvain Medical School, Belgium). T.A.S.D. was supported by the Adams Quan fellowship and by the Harvard Center for Neurodegeneration and Repair. J.S.L. was supported by the Clinical Investigator Training Program: Beth Israel Deaconess Medical Center—Harvard/MIT Health Sciences and Technology, in collaboration with Pfizer Inc. and Merck & Co. S.-Y.Y. is a postdoctoral research associate, and C.A.W. is an Investigator of the Howard Hughes Institute of Medicine. C.A.W. was supported by National Institute of Neurological Disorders and Stroke (P01 NS40043).
PY - 2006/1/5
Y1 - 2006/1/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=29544450409&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2005.10.038
DO - 10.1016/j.neuron.2005.10.038
M3 - Article
C2 - 16387638
AN - SCOPUS:29544450409
SN - 0896-6273
VL - 49
SP - 41
EP - 53
JO - Neuron
JF - Neuron
IS - 1
ER -