Control of species-dependent cortico-motoneuronal connections underlying manual dexterity
Zirong GuJohn KalambogiasShin YoshiokaWenqi HanZhuo LiYuka Imamura KawasawaSirisha PochareddyZhen LiFuchen LiuXuming XuH. R. Sagara WijeratneMasaki UenoEmily BlatzJoseph SalomoneAtsushi KumanogohMladen‐Roko RašinBrian GebeleinMatthew T. WeirauchNenad ŠestanJohn H. MartinYutaka Yoshida
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The disappearance of fine motor control Manual skills are much better developed in primates than in rodents. This difference is in part due to species-specific differences in the control of motoneurons by the brain. Gu et al. used a range of approaches to evaluate potential corticospinal tract projections in neonatal mice. These projections exist immediately after birth but disappear within the first 2 postnatal weeks owing to the actions of plexin A, a member of the semaphorin receptor family. Targeted deletion of semaphorin receptors in mutant mice prevented elimination of corticospinal tract projection and loss of functional monosynaptic input to spinal motoneurons. Science , this issue p. 400Keywords:
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Plexin receptors play a crucial role in the transduction of axonal guidance events elicited by semaphorin proteins. In Drosophila, Plexin A(PlexA) is a receptor for the transmembrane semaphorin semaphorin-1a (Sema-1a)and is required for motor and central nervous system (CNS) axon guidance in the developing embryonic nervous system. However, it remains unknown how PlexB functions during neural development and which ligands serve to activate this receptor. Here, we show that plexB, like plexA, is robustly expressed in the developing CNS and is required for motor and CNS axon pathfinding. PlexB and PlexA serve both distinct and shared neuronal guidance functions. We observe a physical association between these two plexin receptors in vivo and find that they can utilize common downstream signaling mechanisms. PlexB does not directly bind to the cytosolic semaphorin signaling component MICAL (molecule that interacts with CasL), but requires MICAL for certain axonal guidance functions. Ligand binding and genetic analyses demonstrate that PlexB is a receptor for the secreted semaphorin Sema-2a,suggesting that secreted and transmembrane semaphorins in Drosophilause PlexB and PlexA, respectively, for axon pathfinding during neural development. These results establish roles for PlexB in central and peripheral axon pathfinding, define a functional ligand for PlexB, and implicate common signaling events in plexin-mediated axonal guidance.
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Abstract Background Sensory processing relies on projections from the thalamus to the neocortex being established during development. Information from different sensory modalities reaching the thalamus is segregated into specialized nuclei, whose neurons then send inputs to cognate cortical areas through topographically defined axonal connections. Developing thalamocortical axons (TCAs) normally approach the cortex by extending through the subpallium; here, axonal navigation is aided by distributed guidance cues and discrete cell populations, such as the corridor neurons and the internal capsule (IC) guidepost cells. In mice lacking Semaphorin-6A, axons from the dorsal lateral geniculate nucleus (dLGN) bypass the IC and extend aberrantly in the ventral subpallium. The functions normally mediated by Semaphorin-6A in this system remain unknown, but might depend on interactions with Plexin-A2 and Plexin-A4, which have been implicated in other neurodevelopmental processes. Methods We performed immunohistochemical and neuroanatomical analyses of thalamocortical wiring and subpallial development in Sema6a and Plxna2;Plxna4 null mutant mice and analyzed the expression of these genes in relevant structures. Results In Plxna2;Plxna4 double mutants we discovered TCA pathfinding defects that mirrored those observed in Sema6a mutants, suggesting that Semaphorin-6A–Plexin-A2/Plexin-A4 signaling might mediate dLGN axon guidance at subpallial level. In order to understand where and when Semaphorin-6A, Plexin-A2 and Plexin-A4 may be required for proper subpallial TCA guidance, we then characterized their spatiotemporal expression dynamics during early TCA development. We observed that the thalamic neurons whose axons are misrouted in these mutants normally express Semaphorin-6A but not Plexin-A2 or Plexin-A4. By contrast, all three proteins are expressed in corridor cells and other structures in the developing basal ganglia. This could be consistent with the Plexins acting as guidance signals through Sema6A as a receptor on dLGN axons, and/or with an indirect effect on TCA guidance due to functions in morphogenesis of subpallial intermediate targets. In support of the latter possibility, we observed that in both Plxna2;Plxna4 and Sema6a mutants some IC guidepost cells abnormally localize in correspondence of the ventral path misrouted TCAs elongate into. Conclusions These findings implicate Semaphorin-6A–Plexin-A2/Plexin-A4 interactions in dLGN axon guidance and in the spatiotemporal organization of guidepost cell populations in the mammalian subpallium.
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Axons simultaneously encounter multiple guidance cues as they navigate to their targets, but how these different signals are integrated to direct precise steering events is poorly understood. One of our interests is to better characterize a new family of unusual proteins, the MICALs, that play a critical role in transducing the intracellular axon guidance effects of one of the largest families of axon guidance cues, the semaphorins and their plexin receptors. One MICAL interacting protein that was recently identified is the SH3 domain containing protein Cas. Cas proteins stimulate actin filament assembly and integrin‐dependent cell migration in non‐neuronal cells and we have recently found that Cas works together with integrins to direct axon guidance. In the present study, we find that semaphorins and integrins exhibit antagonistic effects on navigating axons that are dependent upon MICAL and Cas. Cas and MICAL proteins are co‐localized in axons and MICAL controls the effectiveness of Cas to mediate axonal guidance. We also find that the regions of MICAL and Cas which facilitate binding are critical for their axon guidance functions. These results reveal a convergence of axon guidance signaling cascades at MICAL and Cas such that plexins signal the repulsion of axons through MICAL and the simultaneous modulation of integrin‐Cas adhesive/permissive axon guidance. Supported by NIH MH069787.
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Sensory processing relies on projections from the thalamus to the neocortex being established during development. Information from different sensory modalities reaching the thalamus is segregated into specialized nuclei, whose neurons then send inputs to cognate cortical areas through topographically defined axonal connections. Developing thalamocortical axons (TCAs) normally approach the cortex by extending through the subpallium; here, axonal navigation is aided by distributed guidance cues and discrete cell populations, such as the corridor neurons and the internal capsule (IC) guidepost cells. In mice lacking Semaphorin-6A, axons from the dorsal lateral geniculate nucleus (dLGN) bypass the IC and extend aberrantly in the ventral subpallium. The functions normally mediated by Semaphorin-6A in this system remain unknown, but might depend on interactions with Plexin-A2 and Plexin-A4, which have been implicated in other neurodevelopmental processes.We performed immunohistochemical and neuroanatomical analyses of thalamocortical wiring and subpallial development in Sema6a and Plxna2; Plxna4 null mutant mice and analyzed the expression of these genes in relevant structures.In Plxna2; Plxna4 double mutants we discovered TCA pathfinding defects that mirrored those observed in Sema6a mutants, suggesting that Semaphorin-6A - Plexin-A2/Plexin-A4 signaling might mediate dLGN axon guidance at subpallial level. In order to understand where and when Semaphorin-6A, Plexin-A2 and Plexin-A4 may be required for proper subpallial TCA guidance, we then characterized their spatiotemporal expression dynamics during early TCA development. We observed that the thalamic neurons whose axons are misrouted in these mutants normally express Semaphorin-6A but not Plexin-A2 or Plexin-A4. By contrast, all three proteins are expressed in corridor cells and other structures in the developing basal ganglia. This finding could be consistent with an hypothetical action of Plexins as guidance signals through Sema6A as a receptor on dLGN axons, and/or with their indirect effect on TCA guidance due to functions in the morphogenesis of subpallial intermediate targets. In support of the latter possibility, we observed that in both Plxna2; Plxna4 and Sema6a mutants some IC guidepost cells abnormally localize in correspondence of the ventral path misrouted TCAs elongate into.These findings implicate Semaphorin-6A - Plexin-A2/Plexin-A4 interactions in dLGN axon guidance and in the spatiotemporal organization of guidepost cell populations in the mammalian subpallium.
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Neocortex
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