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Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism.

Bron R, Vermeren M, Kokot N, Andrews W, Little GE, Mitchell KJ, Cohen J - Neural Dev (2007)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: MRC Centre for Developmental Neurobiology, King's College London, Guy's Campus, London Bridge, London, SE1 1UL, UK. rbron@unimelb.edu.au

ABSTRACT

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 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 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 mouse embryos. In contrast, Sema6A 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.

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Summary of the pathways in motor neurons implicated in mediating a BC cell derived repellent signal that stops somal migration. Boundary cap cells (yellow) located at the MEP express repellent signals (red) that act either directly on motor neuron cell bodies or retrogradely via their axons to disengage somal migration from axon extension. Our data suggest that these signals comprise a combination of class 3 semaphorins and Sema6A (red). Plexin-A2 (purple) expressed by the motor neurons can function as a dual receptor for class 3 and class 6 semaphorins, the former in conjunction with Npn-2 (blue). In this scheme, MICAL3 (green), by linking Plexin-A to the cytoskeleton, is a key downstream mediator of the somal stabilising signal. As a result of cytoskeletal re-organisation, the force (green arrow) exerted from the axonal growth cone that leads to somal translocation in migrating neurons is disrupted.
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Figure 9: Summary of the pathways in motor neurons implicated in mediating a BC cell derived repellent signal that stops somal migration. Boundary cap cells (yellow) located at the MEP express repellent signals (red) that act either directly on motor neuron cell bodies or retrogradely via their axons to disengage somal migration from axon extension. Our data suggest that these signals comprise a combination of class 3 semaphorins and Sema6A (red). Plexin-A2 (purple) expressed by the motor neurons can function as a dual receptor for class 3 and class 6 semaphorins, the former in conjunction with Npn-2 (blue). In this scheme, MICAL3 (green), by linking Plexin-A to the cytoskeleton, is a key downstream mediator of the somal stabilising signal. As a result of cytoskeletal re-organisation, the force (green arrow) exerted from the axonal growth cone that leads to somal translocation in migrating neurons is disrupted.

Mentions: The saltatory motion of migrating immature neurons is dependent on a microtubule perinuclear cage that drags the nucleus and soma unidirectionally [55,56]. Several intracellular proteins are known to be involved in this process and their loss leads to pathologies characterised by ectopic migration, such as lissencephalies and epilepsy [4]. We propose that the effect of the localised semaphorin-PlexinA2-MICAL3 signal that we have identified is to neutralise or provide an opposing force to the axon-driven perinuclear cage drag (Figure 9).


Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism.

Bron R, Vermeren M, Kokot N, Andrews W, Little GE, Mitchell KJ, Cohen J - Neural Dev (2007)

Summary of the pathways in motor neurons implicated in mediating a BC cell derived repellent signal that stops somal migration. Boundary cap cells (yellow) located at the MEP express repellent signals (red) that act either directly on motor neuron cell bodies or retrogradely via their axons to disengage somal migration from axon extension. Our data suggest that these signals comprise a combination of class 3 semaphorins and Sema6A (red). Plexin-A2 (purple) expressed by the motor neurons can function as a dual receptor for class 3 and class 6 semaphorins, the former in conjunction with Npn-2 (blue). In this scheme, MICAL3 (green), by linking Plexin-A to the cytoskeleton, is a key downstream mediator of the somal stabilising signal. As a result of cytoskeletal re-organisation, the force (green arrow) exerted from the axonal growth cone that leads to somal translocation in migrating neurons is disrupted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2131750&req=5

Figure 9: Summary of the pathways in motor neurons implicated in mediating a BC cell derived repellent signal that stops somal migration. Boundary cap cells (yellow) located at the MEP express repellent signals (red) that act either directly on motor neuron cell bodies or retrogradely via their axons to disengage somal migration from axon extension. Our data suggest that these signals comprise a combination of class 3 semaphorins and Sema6A (red). Plexin-A2 (purple) expressed by the motor neurons can function as a dual receptor for class 3 and class 6 semaphorins, the former in conjunction with Npn-2 (blue). In this scheme, MICAL3 (green), by linking Plexin-A to the cytoskeleton, is a key downstream mediator of the somal stabilising signal. As a result of cytoskeletal re-organisation, the force (green arrow) exerted from the axonal growth cone that leads to somal translocation in migrating neurons is disrupted.
Mentions: The saltatory motion of migrating immature neurons is dependent on a microtubule perinuclear cage that drags the nucleus and soma unidirectionally [55,56]. Several intracellular proteins are known to be involved in this process and their loss leads to pathologies characterised by ectopic migration, such as lissencephalies and epilepsy [4]. We propose that the effect of the localised semaphorin-PlexinA2-MICAL3 signal that we have identified is to neutralise or provide an opposing force to the axon-driven perinuclear cage drag (Figure 9).

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: MRC Centre for Developmental Neurobiology, King's College London, Guy's Campus, London Bridge, London, SE1 1UL, UK. rbron@unimelb.edu.au

ABSTRACT

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 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 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 mouse embryos. In contrast, Sema6A 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.

Show MeSH
Related in: MedlinePlus