Semaphorin Signaling During Cardiac Development
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Keywords:
Plexin
Fasciculation
Cardiac muscle
Plexin
Neuropilin
SEMA3A
Growth cone
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In early development, an excess of neurons is generated, of which later about half will be lost by cell death due to a limited supply of trophic support by their respective target areas. However, some of the neurons die when their axons have not yet reached their target, thus suggesting that additional causes of developmental cell death exist. Semaphorin 3A (Sema3A), in addition to its function as a guidance cue and mediator of timing and fasciculation of motor and sensory axon outgrowth, can also induce death of sensory neurons in vitro. However, it is unknown whether Neuropilin-1 (Npn-1), its binding receptor in axon guidance, also mediates the death-inducing activity. We show here that abolished Sema3A-Npn-1 signaling does not influence the cell death patterns of motor or sensory neurons in mouse during the developmental wave of programmed cell death. The number of motor and sensory neurons was unchanged at embryonic day 15.5 when this wave is concluded. Interestingly, the defasciculation of early motor and sensory projections that is observed in the absence of Sema3A or Npn-1 persists to postnatal stages. Thus, Sema3A-Npn-1 signaling plays an important role in the guidance and fasciculation of motor and sensory axons but does not contribute to the developmental elimination of these neurons.
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Dorsal root ganglion
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Dorsal root ganglion
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Plexin
Neuropilin
Synaptogenesis
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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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Growth cone
Neural Development
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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.
Plexin
Neocortex
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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.
Plexin
Neocortex
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