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Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism
BACKGROUND: In developing neurons, somal migration and initiation of axon outgrowth often occur simultaneously and are regulated in part by similar classes of molecules. When neurons reach their final destinations, however, somal translocation and axon extension are uncoupled. Insights into the mech...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2007
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2131750/ https://www.ncbi.nlm.nih.gov/pubmed/17971221 http://dx.doi.org/10.1186/1749-8104-2-21 |
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author | Bron, Romke Vermeren, Matthieu Kokot, Natalie Andrews, William Little, Graham E Mitchell, Kevin J Cohen, James |
author_facet | Bron, Romke Vermeren, Matthieu Kokot, Natalie Andrews, William Little, Graham E Mitchell, Kevin J Cohen, James |
author_sort | Bron, Romke |
collection | PubMed |
description | BACKGROUND: In developing neurons, somal migration and initiation of axon outgrowth often occur simultaneously and are regulated in part by similar classes of molecules. When neurons reach their final destinations, however, somal translocation and axon extension are uncoupled. Insights into the mechanisms underlying this process of disengagement came from our study of the behaviour of embryonic spinal motor neurons following ablation of boundary cap cells. These are neural crest derivatives that transiently reside at motor exit points, central nervous system (CNS):peripheral nervous system (PNS) interfaces where motor axons leave the CNS. In the absence of boundary cap cells, motor neuron cell bodies migrate along their axons into the periphery, suggesting that repellent signals from boundary cap cells regulate the selective gating of somal migration and axon outgrowth at the motor exit point. Here we used RNA interference in the chick embryo together with analysis of null mutant mice to identify possible boundary cap cell ligands, their receptors on motor neurons and cytoplasmic signalling molecules that control this process. RESULTS: We demonstrate that targeted knock down in motor neurons of Neuropilin-2 (Npn-2), a high affinity receptor for class 3 semaphorins, causes their somata to migrate to ectopic positions in ventral nerve roots. This finding was corroborated in Npn-2 null mice, in which we identified motor neuron cell bodies in ectopic positions in the PNS. Our RNA interference studies further revealed a role for Plexin-A2, but not Plexin-A1 or Plexin-A4. We show that chick and mouse boundary cap cells express Sema3B and 3G, secreted semaphorins, and Sema6A, a transmembrane semaphorin. However, no increased numbers of ectopic motor neurons are found in Sema3B null mouse embryos. In contrast, Sema6A null mice display an ectopic motor neuron phenotype. Finally, knockdown of MICAL3, a downstream semaphorin/Plexin-A signalling molecule, in chick motor neurons led to their ectopic positioning in the PNS. CONCLUSION: We conclude that semaphorin-mediated repellent interactions between boundary cap cells and immature spinal motor neurons regulates somal positioning by countering the drag exerted on motor neuron cell bodies by their axons as they emerge from the CNS at motor exit points. Our data support a model in which BC cell semaphorins signal through Npn-2 and/or Plexin-A2 receptors on motor neurons via a cytoplasmic effector, MICAL3, to trigger cytoskeletal reorganisation. This leads to the disengagement of somal migration from axon extension and the confinement of motor neuron cell bodies to the spinal cord. |
format | Text |
id | pubmed-2131750 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-21317502007-12-12 Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism Bron, Romke Vermeren, Matthieu Kokot, Natalie Andrews, William Little, Graham E Mitchell, Kevin J Cohen, James Neural Develop Research Article BACKGROUND: In developing neurons, somal migration and initiation of axon outgrowth often occur simultaneously and are regulated in part by similar classes of molecules. When neurons reach their final destinations, however, somal translocation and axon extension are uncoupled. Insights into the mechanisms underlying this process of disengagement came from our study of the behaviour of embryonic spinal motor neurons following ablation of boundary cap cells. These are neural crest derivatives that transiently reside at motor exit points, central nervous system (CNS):peripheral nervous system (PNS) interfaces where motor axons leave the CNS. In the absence of boundary cap cells, motor neuron cell bodies migrate along their axons into the periphery, suggesting that repellent signals from boundary cap cells regulate the selective gating of somal migration and axon outgrowth at the motor exit point. Here we used RNA interference in the chick embryo together with analysis of null mutant mice to identify possible boundary cap cell ligands, their receptors on motor neurons and cytoplasmic signalling molecules that control this process. RESULTS: We demonstrate that targeted knock down in motor neurons of Neuropilin-2 (Npn-2), a high affinity receptor for class 3 semaphorins, causes their somata to migrate to ectopic positions in ventral nerve roots. This finding was corroborated in Npn-2 null mice, in which we identified motor neuron cell bodies in ectopic positions in the PNS. Our RNA interference studies further revealed a role for Plexin-A2, but not Plexin-A1 or Plexin-A4. We show that chick and mouse boundary cap cells express Sema3B and 3G, secreted semaphorins, and Sema6A, a transmembrane semaphorin. However, no increased numbers of ectopic motor neurons are found in Sema3B null mouse embryos. In contrast, Sema6A null mice display an ectopic motor neuron phenotype. Finally, knockdown of MICAL3, a downstream semaphorin/Plexin-A signalling molecule, in chick motor neurons led to their ectopic positioning in the PNS. CONCLUSION: We conclude that semaphorin-mediated repellent interactions between boundary cap cells and immature spinal motor neurons regulates somal positioning by countering the drag exerted on motor neuron cell bodies by their axons as they emerge from the CNS at motor exit points. Our data support a model in which BC cell semaphorins signal through Npn-2 and/or Plexin-A2 receptors on motor neurons via a cytoplasmic effector, MICAL3, to trigger cytoskeletal reorganisation. This leads to the disengagement of somal migration from axon extension and the confinement of motor neuron cell bodies to the spinal cord. BioMed Central 2007-10-30 /pmc/articles/PMC2131750/ /pubmed/17971221 http://dx.doi.org/10.1186/1749-8104-2-21 Text en Copyright © 2007 Bron et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Bron, Romke Vermeren, Matthieu Kokot, Natalie Andrews, William Little, Graham E Mitchell, Kevin J Cohen, James Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism |
title | Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism |
title_full | Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism |
title_fullStr | Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism |
title_full_unstemmed | Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism |
title_short | Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism |
title_sort | boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2131750/ https://www.ncbi.nlm.nih.gov/pubmed/17971221 http://dx.doi.org/10.1186/1749-8104-2-21 |
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