期刊
NEURON
卷 106, 期 2, 页码 246-+出版社
CELL PRESS
DOI: 10.1016/j.neuron.2020.01.030
关键词
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资金
- Manton Center for Orphan Disease Research from the NINDS [R01NS035129, R01NS032457]
- Allen Discovery Center program through The Paul G. Allen Frontiers Group
- William Randolph Hearst Fund
- Charles Hood Foundation
- Child Health Research Career Development Award Program [K12 HD052896]
- NIH [T32GM007753]
- HCBI Simmons Award
- National Human Genome Research Institute
- National Eye Institute
- National Heart, Lung and Blood Institute [UM1 HG008900]
- Australian Genomics Health Alliance [GNT1113531]
- NHMRC, a Maurice de Rohan international scholarship
- Australian Government Research Training Program scholarship
- National Science Centre, Poland [2015/19/B/NZ2/01824]
- [R21NS104633-01A1]
Genes mutated in human neuronal migration disorders encode tubulin proteins and a variety of tubulin-binding and -regulating proteins, but it is very poorly understood how these proteins function together to coordinate migration. Additionally, the way in which regional differences in neocortical migration are controlled is completely unknown. Here we describe a new syndrome with remarkably region-specific effects on neuronal migration in the posterior cortex, reflecting de novo variants in CEP85L. We show that CEP85L is required cell autonomously in vivo and in vitro for migration, that it localizes to the maternal centriole, and that it forms a complex with many other proteins required for migration, including CDK5, LIS1, NDE1, KIF2A, and DYNC1H1. Loss of CEP85L disrupts CDK5 localization and activation, leading to centrosome disorganization and disrupted microtubule cytoskeleton organization. Together, our findings suggest that CEP85L highlights a complex that controls CDK5 activity to promote neuronal migration.
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