Abstract
BackgroundSensory 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.MethodsWe 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.ResultsIn 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.ConclusionsThese 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.
Highlights
Sensory processing relies on projections from the thalamus to the neocortex being established during development
Plxna2; Plxna4 double mutant mice show defects in subpallial Thalamocortical axon (TCA) guidance In order to analyze the development of thalamocortical connections in Plxna2 and Plxna4 mutant mouse brains, immunohistochemistry for the 165 kDa neurofilament subunit, a pan-axonal marker, was first performed on Plxna2−/−, Plxna4+/+, Plxna2+/+, Plxna4−/−, Plxna2+/−; Plxna4+/−, Plxna2+/−; Plxna4−/−, Plxna2−/−; Plxna4+/−, and Plxna2−/−; Plxna4−/− early postnatal littermate brains (n ≥ 3 for all genotypes analyzed) (Fig. 1)
Plxna2−/−; Plxna4−/− mice were found to present a Detailed analysis of the trajectories followed by the misrouted TCAs highlighted the presence, as in Sema6a mutants, of two discrete TCA bundles extending in distinct pathways in the ventral telencephalon (vTel)
Summary
Sensory processing relies on projections from the thalamus to the neocortex being established during development. While a wealth of knowledge has been gained in the past two decades on axon guidance molecules and their roles in steering developing axons, our understanding of the processes underlying intermediate target formation, guidance cue patterning of axonal pathways, and cue presentation to elongating fibers is still relatively limited [22, 24]. One of these process is the migration at intermediate points of “guidepost cells”, i.e., discrete, specialized cell populations that finely orient growth cones via short-range cues and direct cell–cell contacts. Several lines of evidence have pointed to a role of guidance factors in guidepost cell migration and positioning, and have shown how these molecules can affect axonal pathfinding in an indirect manner (reviewed in Squarzoni, Thion [25])
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