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.

Authors

Andrew Kodani¹, Connor Kenny², Abbe Lai³, Dilenny M Gonzalez², Edward Stronge², Gabrielle M Sejourne², Laura Isacco², Jennifer N Partlow², Anne O'Donnell⁴, Kirsty McWalter⁵, Alicia B Byrne⁶, A James Barkovich⁷, Edward Yang⁸, R Sean Hill², Pawel Gawlinski⁹, Wojciech Wiszniewski¹⁰, Julie S Cohen¹¹, S Ali Fatemi¹², Kristin W Baranano¹¹, Mustafa Sahin¹³, David G Vossler¹⁴, Christopher J Yuskaitis¹⁵, Christopher A Walsh¹⁶

Affiliations

¹ Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA. Electronic address: andrew.kodani@childrens.harvard.edu.
² Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA.
³ Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
⁴ Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA; Center for Mendelian Genomics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ GeneDX, Gaithersburg, MD, USA.
⁶ Center for Mendelian Genomics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
⁷ Department of Radiology, University of California, San Francisco, San Francisco, CA, USA.
⁸ Department of Radiology, Boston Children's Hospital, Boston, MA, USA.
⁹ Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
¹⁰ Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
¹¹ Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
¹⁴ Department of Neurology, University of Washington, Seattle, WA, USA.
¹⁵ Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
¹⁶ Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA. Electronic address: christopher.walsh@childrens.harvard.edu.

Abstract

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding