Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5

Neuron. 2020 Apr 22;106(2):246-255.e6. doi: 10.1016/j.neuron.2020.01.030. Epub 2020 Feb 24.


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.

Keywords: CDK5; CEP85L; Centrosome; De novo; Lissencephaly; Pachygyria; genetics; neurodevelopment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Movement*
  • Centrioles / genetics
  • Child
  • Child, Preschool
  • Cyclin-Dependent Kinase 5 / genetics*
  • Cytoskeletal Proteins / genetics*
  • Female
  • Humans
  • Lissencephaly / genetics*
  • Lissencephaly / pathology*
  • Male
  • Microtubules / genetics
  • Microtubules / ultrastructure
  • Neocortex / pathology*
  • Nerve Tissue Proteins / physiology
  • Neurons / pathology*
  • Oncogene Proteins, Fusion / genetics*
  • Young Adult


  • CEP85L protein, human
  • Cytoskeletal Proteins
  • Nerve Tissue Proteins
  • Oncogene Proteins, Fusion
  • Cyclin-Dependent Kinase 5
  • CDK5 protein, human