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

Andrew Kodani; Connor Kenny; Abbe Lai; Dilenny M. Gonzalez; Edward Stronge; Gabrielle M. Sejourne; Laura Isacco; Jennifer N. Partlow; Anne O'Donnell; Kirsty McWalter; Alicia B. Byrne; A. James Barkovich; Edward Yang; R. Sean Hill; Pawel Gawlinski; Wojciech Wiszniewski; Julie S. Cohen; S. Ali Fatemi; Kristin W. Baranano; Mustafa Sahin; David G. Vossler; Christopher J. Yuskaitis; Christopher A. Walsh

doi:10.1016/j.neuron.2020.01.030

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

Andrew Kodani, Connor Kenny, Abbe Lai, Dilenny M. Gonzalez, Edward Stronge, Gabrielle M. Sejourne, Laura Isacco, Jennifer N. Partlow, Anne O'Donnell, Kirsty McWalter, Alicia B. Byrne, A. James Barkovich, Edward Yang, R. Sean Hill, Pawel Gawlinski, Wojciech Wiszniewski, Julie S. Cohen, S. Ali Fatemi, Kristin W. Baranano, Mustafa SahinDavid G. Vossler, Christopher J. Yuskaitis, Christopher A. Walsh

School of Medicine

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Pages (from-to)	246-255.e6
Journal	Neuron
Volume	106
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2020.01.030
State	Published - Apr 22 2020

Keywords

CDK5
CEP85L
Centrosome
De novo
Lissencephaly
Pachygyria
genetics
neurodevelopment

ASJC Scopus subject areas

Neuroscience(all)

Access to Document

10.1016/j.neuron.2020.01.030

Cite this

Kodani, A., Kenny, C., Lai, A., Gonzalez, D. M., Stronge, E., Sejourne, G. M., Isacco, L., Partlow, J. N., O'Donnell, A., McWalter, K., Byrne, A. B., Barkovich, A. J., Yang, E., Hill, R. S., Gawlinski, P., Wiszniewski, W., Cohen, J. S., Fatemi, S. A., Baranano, K. W., ... Walsh, C. A. (2020). Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5. Neuron, 106(2), 246-255.e6. https://doi.org/10.1016/j.neuron.2020.01.030

Kodani, A, Kenny, C, Lai, A, Gonzalez, DM, Stronge, E, Sejourne, GM, Isacco, L, Partlow, JN, O'Donnell, A, McWalter, K, Byrne, AB, Barkovich, AJ, Yang, E, Hill, RS, Gawlinski, P, Wiszniewski, W, Cohen, JS, Fatemi, SA, Baranano, KW, Sahin, M, Vossler, DG, Yuskaitis, CJ & Walsh, CA 2020, 'Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5', Neuron, vol. 106, no. 2, pp. 246-255.e6. https://doi.org/10.1016/j.neuron.2020.01.030

@article{b7fc606a69c04a92a52bd4d392a69fd6,

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

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",

author = "Andrew Kodani and Connor Kenny and Abbe Lai and Gonzalez, {Dilenny M.} and Edward Stronge and Sejourne, {Gabrielle M.} and Laura Isacco and Partlow, {Jennifer N.} and Anne O'Donnell and Kirsty McWalter and Byrne, {Alicia B.} and Barkovich, {A. James} and Edward Yang and Hill, {R. Sean} and Pawel Gawlinski and Wojciech Wiszniewski and Cohen, {Julie S.} and Fatemi, {S. Ali} and Baranano, {Kristin W.} and Mustafa Sahin and Vossler, {David G.} and Yuskaitis, {Christopher J.} and Walsh, {Christopher A.}",

note = "Funding Information: The authors thank the families for their invaluable participation in our study. We thank Drs. Douglas Lowy, Brajendra Tripathi, Daniella Magen, and Andrew Holland for cell lines and antibodies. We also thank Drs. Meng-Fu Bryan Tsou and Laurence Pelletier for insightful discussions. C.A.W. was supported by The Manton Center for Orphan Disease Research, R01NS035129 and R01NS032457 from the NINDS, and the Allen Discovery Center program through The Paul G. Allen Frontiers Group. C.A.W. is an Investigator of the Howard Hughes Medical Institute. A.K. was supported by R21NS104633-01A1, the William Randolph Hearst Fund, and the Charles Hood Foundation. A.O. was supported by the K12 HD052896 Child Health Research Career Development Award Program. E.S. was supported by NIH T32GM007753 and the HCBI Simmons Award. Sequencing and analysis for PAC2801, LIS6801, DC7401, and PAC3301 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute, and National Heart, Lung and Blood Institute grant UM1 HG008900 (to Daniel MacArthur and Heidi Rehm). A.B. was supported by GNT1113531 from the Australian Genomics Health Alliance and NHMRC, a Maurice de Rohan international scholarship, and an Australian Government Research Training Program scholarship. GeneDx Inc. performed a trio exome on LIS7901, and a connection was made via MatchMaker Exchange. The work done for 40291IMID was supported by the National Science Centre, Poland 2015/19/B/NZ2/01824 (to W.W.), and exome sequencing was performed at the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine through the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) initiative. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The project was conceived by A.K. and C.A.W. and the experiments were carried out by A.K. C.K. and A.L. had comparable contributions to this study regarding cell biology and genetics, respectively. D.M.G. and L.I. performed in utero electroporation. E.S. performed qPCR in human tissue. G.M.S. helped analyze scratch wound assays. Participant enrollment, sample collection, and phenotype review were performed by A.L. J.N.P. A.B.B. A.J.B. E.Y. R.S.H. P.G. W.W. J.S.C. S.A.F. C.J.Y. M.S. K.W.B. D.G.V. and C.A.W. Data analysis was performed by A.K. C.K. D.M.G. G.M.S. and L.I. The manuscript was written by A.K. with help from the other authors. All aspects of the study were supervised by A.K. and C.A.W. C.A.W. serves on advisory boards for the Allen Brain Institute, Third Rock Ventures, and Maze Therapeutics and on editorial boards for Annals of Neurology, Trends in Neurosciences, and neuroDEVELOPMENTS. M.S. received research funding from Roche, Novartis, Pfizer, LAM Therapeutics, and Quadrant Biosciences; has served on the scientific advisory boards of Sage Therapeutics, Roche, Takeda, Celgene, and the PTEN Research Foundation; and serves on the Board of the Tuberous Sclerosis Alliance. All of these activities are outside of the submitted manuscript. J.S.C. is a consultant for Invitae. D.V. serves as a consultant to SK Life Science and Otsuka Pharmaceuticals, is on the speaker's bureaus for UCB and Greenwich Pharmaceuticals, and conducts industry-supported clinical drug trials for SK Life Science, Biogen, and UCB Pharmaceuticals. K.M. is an employee of GeneDX, Inc. Funding Information: The authors thank the families for their invaluable participation in our study. We thank Drs. Douglas Lowy, Brajendra Tripathi, Daniella Magen, and Andrew Holland for cell lines and antibodies. We also thank Drs. Meng-Fu Bryan Tsou and Laurence Pelletier for insightful discussions. C.A.W. was supported by The Manton Center for Orphan Disease Research , R01NS035129 and R01NS032457 from the NINDS , and the Allen Discovery Center program through The Paul G. Allen Frontiers Group . C.A.W. is an Investigator of the Howard Hughes Medical Institute. A.K. was supported by R21NS104633-01A1 , the William Randolph Hearst Fund , and the Charles Hood Foundation . A.O. was supported by the K12 HD052896 Child Health Research Career Development Award Program . E.S. was supported by NIH T32GM007753 and the HCBI Simmons Award. Sequencing and analysis for PAC2801, LIS6801, DC7401, and PAC3301 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute , the National Eye Institute , and National Heart, Lung and Blood Institute grant UM1 HG008900 (to Daniel MacArthur and Heidi Rehm). A.B. was supported by GNT1113531 from the Australian Genomics Health Alliance and NHMRC , a Maurice de Rohan international scholarship, and an Australian Government Research Training Program scholarship. GeneDx Inc. performed a trio exome on LIS7901, and a connection was made via MatchMaker Exchange. The work done for 40291IMID was supported by the National Science Centre, Poland 2015/19/B/NZ2/01824 (to W.W.), and exome sequencing was performed at the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine through the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) initiative. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = apr,

day = "22",

doi = "10.1016/j.neuron.2020.01.030",

language = "English (US)",

volume = "106",

pages = "246--255.e6",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5

AU - Kodani, Andrew

AU - Kenny, Connor

AU - Lai, Abbe

AU - Gonzalez, Dilenny M.

AU - Stronge, Edward

AU - Sejourne, Gabrielle M.

AU - Isacco, Laura

AU - Partlow, Jennifer N.

AU - O'Donnell, Anne

AU - McWalter, Kirsty

AU - Byrne, Alicia B.

AU - Barkovich, A. James

AU - Yang, Edward

AU - Hill, R. Sean

AU - Gawlinski, Pawel

AU - Wiszniewski, Wojciech

AU - Cohen, Julie S.

AU - Fatemi, S. Ali

AU - Baranano, Kristin W.

AU - Sahin, Mustafa

AU - Vossler, David G.

AU - Yuskaitis, Christopher J.

AU - Walsh, Christopher A.

N1 - Funding Information: The authors thank the families for their invaluable participation in our study. We thank Drs. Douglas Lowy, Brajendra Tripathi, Daniella Magen, and Andrew Holland for cell lines and antibodies. We also thank Drs. Meng-Fu Bryan Tsou and Laurence Pelletier for insightful discussions. C.A.W. was supported by The Manton Center for Orphan Disease Research, R01NS035129 and R01NS032457 from the NINDS, and the Allen Discovery Center program through The Paul G. Allen Frontiers Group. C.A.W. is an Investigator of the Howard Hughes Medical Institute. A.K. was supported by R21NS104633-01A1, the William Randolph Hearst Fund, and the Charles Hood Foundation. A.O. was supported by the K12 HD052896 Child Health Research Career Development Award Program. E.S. was supported by NIH T32GM007753 and the HCBI Simmons Award. Sequencing and analysis for PAC2801, LIS6801, DC7401, and PAC3301 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute, and National Heart, Lung and Blood Institute grant UM1 HG008900 (to Daniel MacArthur and Heidi Rehm). A.B. was supported by GNT1113531 from the Australian Genomics Health Alliance and NHMRC, a Maurice de Rohan international scholarship, and an Australian Government Research Training Program scholarship. GeneDx Inc. performed a trio exome on LIS7901, and a connection was made via MatchMaker Exchange. The work done for 40291IMID was supported by the National Science Centre, Poland 2015/19/B/NZ2/01824 (to W.W.), and exome sequencing was performed at the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine through the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) initiative. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The project was conceived by A.K. and C.A.W. and the experiments were carried out by A.K. C.K. and A.L. had comparable contributions to this study regarding cell biology and genetics, respectively. D.M.G. and L.I. performed in utero electroporation. E.S. performed qPCR in human tissue. G.M.S. helped analyze scratch wound assays. Participant enrollment, sample collection, and phenotype review were performed by A.L. J.N.P. A.B.B. A.J.B. E.Y. R.S.H. P.G. W.W. J.S.C. S.A.F. C.J.Y. M.S. K.W.B. D.G.V. and C.A.W. Data analysis was performed by A.K. C.K. D.M.G. G.M.S. and L.I. The manuscript was written by A.K. with help from the other authors. All aspects of the study were supervised by A.K. and C.A.W. C.A.W. serves on advisory boards for the Allen Brain Institute, Third Rock Ventures, and Maze Therapeutics and on editorial boards for Annals of Neurology, Trends in Neurosciences, and neuroDEVELOPMENTS. M.S. received research funding from Roche, Novartis, Pfizer, LAM Therapeutics, and Quadrant Biosciences; has served on the scientific advisory boards of Sage Therapeutics, Roche, Takeda, Celgene, and the PTEN Research Foundation; and serves on the Board of the Tuberous Sclerosis Alliance. All of these activities are outside of the submitted manuscript. J.S.C. is a consultant for Invitae. D.V. serves as a consultant to SK Life Science and Otsuka Pharmaceuticals, is on the speaker's bureaus for UCB and Greenwich Pharmaceuticals, and conducts industry-supported clinical drug trials for SK Life Science, Biogen, and UCB Pharmaceuticals. K.M. is an employee of GeneDX, Inc. Funding Information: The authors thank the families for their invaluable participation in our study. We thank Drs. Douglas Lowy, Brajendra Tripathi, Daniella Magen, and Andrew Holland for cell lines and antibodies. We also thank Drs. Meng-Fu Bryan Tsou and Laurence Pelletier for insightful discussions. C.A.W. was supported by The Manton Center for Orphan Disease Research , R01NS035129 and R01NS032457 from the NINDS , and the Allen Discovery Center program through The Paul G. Allen Frontiers Group . C.A.W. is an Investigator of the Howard Hughes Medical Institute. A.K. was supported by R21NS104633-01A1 , the William Randolph Hearst Fund , and the Charles Hood Foundation . A.O. was supported by the K12 HD052896 Child Health Research Career Development Award Program . E.S. was supported by NIH T32GM007753 and the HCBI Simmons Award. Sequencing and analysis for PAC2801, LIS6801, DC7401, and PAC3301 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute , the National Eye Institute , and National Heart, Lung and Blood Institute grant UM1 HG008900 (to Daniel MacArthur and Heidi Rehm). A.B. was supported by GNT1113531 from the Australian Genomics Health Alliance and NHMRC , a Maurice de Rohan international scholarship, and an Australian Government Research Training Program scholarship. GeneDx Inc. performed a trio exome on LIS7901, and a connection was made via MatchMaker Exchange. The work done for 40291IMID was supported by the National Science Centre, Poland 2015/19/B/NZ2/01824 (to W.W.), and exome sequencing was performed at the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine through the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) initiative. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/4/22

Y1 - 2020/4/22

N2 - 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.

AB - 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.

KW - CDK5

KW - CEP85L

KW - Centrosome

KW - De novo

KW - Lissencephaly

KW - Pachygyria

KW - genetics

KW - neurodevelopment

UR - http://www.scopus.com/inward/record.url?scp=85083306241&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85083306241&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2020.01.030

DO - 10.1016/j.neuron.2020.01.030

M3 - Article

C2 - 32097629

AN - SCOPUS:85083306241

SN - 0896-6273

VL - 106

SP - 246-255.e6

JO - Neuron

JF - Neuron

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this