Recruitment of katanin p60 by phosphorylated NDEL1, an LIS1 interacting protein, is essential for mitotic cell division and neuronal migration.
LIS1 is mutated in the human neuronal migration defect lissencephaly and along with NDEL1 (formerly NUDEL) participates in the regulation of cytoplasmic dynein function during neuronal development. Targeted disruption of Ndel1 suggested that NDEL1 could have other molecular targets that regulate microtubule organization for proper neuronal migration. To further understanding the molecular mechanism of LIS1 and lissencephaly, we identified the katanin p60 microtubule-severing protein as an additional molecular target of NDEL1. We demonstrate that phosphorylation of NDEL1 by Cdk5 facilitates interaction between NDEL1 and p60, suggesting that P-NDEL1 regulates the distribution of katanin p60. Abnormal accumulation of p60 in nucleus of Ndel1 null mutants supports an essential role of NDEL1 in p60 regulation. Complete loss of NDEL1 or expression of dominant negative mutants of p60 in migrating neurons results in defective migration and elongation of nuclear-centrosomal distance. Our results suggest that NDEL1 is essential for mitotic cell division and neuronal migration not only via regulation of cytoplasmic dynein function but also by modulation of katanin p60 localization and function.
Toyo-Oka
Kazuhito
K
Department of Genetic Disease Research, Osaka University Graduate School of Medicine, Japan.
Sasaki
Shinji
S
Yano
Yoshihisa
Y
Mori
Daisuke
D
Kobayashi
Takuya
T
Toyoshima
Yoko Y
YY
Tokuoka
Suzumi M
SM
Ishii
Satoshi
S
Shimizu
Takao
T
Muramatsu
Masami
M
Hiraiwa
Noriko
N
Yoshiki
Atsushi
A
Wynshaw-Boris
Anthony
A
Hirotsune
Shinji
S
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D000074201:Katanin; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D010766:Phosphorylation; D020798:Two-Hybrid System Techniques; D015003:Yeasts
D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; C421108:NDEL1 protein, human; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; D000251:Adenosine Triphosphatases; D004398:Dyneins; D000074201:Katanin