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Dynein activating adaptor BICD2 controls radial migration of upper-layer cortical neurons in vivo

For the proper organization of the six-layered mammalian neocortex it is required that neurons migrate radially from their place of birth towards their designated destination. The molecular machinery underlying this neuronal migration is still poorly understood. The dynein-adaptor protein BICD2 is a...

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Autores principales: Will, Lena, Portegies, Sybren, van Schelt, Jasper, van Luyk, Merel, Jaarsma, Dick, Hoogenraad, Casper C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815425/
https://www.ncbi.nlm.nih.gov/pubmed/31655624
http://dx.doi.org/10.1186/s40478-019-0827-y
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author Will, Lena
Portegies, Sybren
van Schelt, Jasper
van Luyk, Merel
Jaarsma, Dick
Hoogenraad, Casper C.
author_facet Will, Lena
Portegies, Sybren
van Schelt, Jasper
van Luyk, Merel
Jaarsma, Dick
Hoogenraad, Casper C.
author_sort Will, Lena
collection PubMed
description For the proper organization of the six-layered mammalian neocortex it is required that neurons migrate radially from their place of birth towards their designated destination. The molecular machinery underlying this neuronal migration is still poorly understood. The dynein-adaptor protein BICD2 is associated with a spectrum of human neurological diseases, including malformations of cortical development. Previous studies have shown that knockdown of BICD2 interferes with interkinetic nuclear migration in radial glial progenitor cells, and that Bicd2-deficient mice display an altered laminar organization of the cerebellum and the neocortex. However, the precise in vivo role of BICD2 in neocortical development remains unclear. By comparing cell-type specific conditional Bicd2 knock-out mice, we found that radial migration in the cortex predominantly depends on BICD2 function in post-mitotic neurons. Neuron-specific Bicd2 cKO mice showed severely impaired radial migration of late-born upper-layer neurons. BICD2 depletion in cortical neurons interfered with proper Golgi organization, and neuronal maturation and survival of cortical plate neurons. Single-neuron labeling revealed a specific role of BICD2 in bipolar locomotion. Rescue experiments with wildtype and disease-related mutant BICD2 constructs revealed that a point-mutation in the RAB6/RANBP2-binding-domain, associated with cortical malformation in patients, fails to restore proper cortical neuron migration. Together, these findings demonstrate a novel, cell-intrinsic role of BICD2 in cortical neuron migration in vivo and provide new insights into BICD2-dependent dynein-mediated functions during cortical development.
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spelling pubmed-68154252019-10-31 Dynein activating adaptor BICD2 controls radial migration of upper-layer cortical neurons in vivo Will, Lena Portegies, Sybren van Schelt, Jasper van Luyk, Merel Jaarsma, Dick Hoogenraad, Casper C. Acta Neuropathol Commun Research For the proper organization of the six-layered mammalian neocortex it is required that neurons migrate radially from their place of birth towards their designated destination. The molecular machinery underlying this neuronal migration is still poorly understood. The dynein-adaptor protein BICD2 is associated with a spectrum of human neurological diseases, including malformations of cortical development. Previous studies have shown that knockdown of BICD2 interferes with interkinetic nuclear migration in radial glial progenitor cells, and that Bicd2-deficient mice display an altered laminar organization of the cerebellum and the neocortex. However, the precise in vivo role of BICD2 in neocortical development remains unclear. By comparing cell-type specific conditional Bicd2 knock-out mice, we found that radial migration in the cortex predominantly depends on BICD2 function in post-mitotic neurons. Neuron-specific Bicd2 cKO mice showed severely impaired radial migration of late-born upper-layer neurons. BICD2 depletion in cortical neurons interfered with proper Golgi organization, and neuronal maturation and survival of cortical plate neurons. Single-neuron labeling revealed a specific role of BICD2 in bipolar locomotion. Rescue experiments with wildtype and disease-related mutant BICD2 constructs revealed that a point-mutation in the RAB6/RANBP2-binding-domain, associated with cortical malformation in patients, fails to restore proper cortical neuron migration. Together, these findings demonstrate a novel, cell-intrinsic role of BICD2 in cortical neuron migration in vivo and provide new insights into BICD2-dependent dynein-mediated functions during cortical development. BioMed Central 2019-10-26 /pmc/articles/PMC6815425/ /pubmed/31655624 http://dx.doi.org/10.1186/s40478-019-0827-y Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Will, Lena
Portegies, Sybren
van Schelt, Jasper
van Luyk, Merel
Jaarsma, Dick
Hoogenraad, Casper C.
Dynein activating adaptor BICD2 controls radial migration of upper-layer cortical neurons in vivo
title Dynein activating adaptor BICD2 controls radial migration of upper-layer cortical neurons in vivo
title_full Dynein activating adaptor BICD2 controls radial migration of upper-layer cortical neurons in vivo
title_fullStr Dynein activating adaptor BICD2 controls radial migration of upper-layer cortical neurons in vivo
title_full_unstemmed Dynein activating adaptor BICD2 controls radial migration of upper-layer cortical neurons in vivo
title_short Dynein activating adaptor BICD2 controls radial migration of upper-layer cortical neurons in vivo
title_sort dynein activating adaptor bicd2 controls radial migration of upper-layer cortical neurons in vivo
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815425/
https://www.ncbi.nlm.nih.gov/pubmed/31655624
http://dx.doi.org/10.1186/s40478-019-0827-y
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