Semaphorin-Plexin signaling influences early ventral telencephalic development and thalamocortical axon guidance

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-017-0083-4) contains supplementary material, which is available to authorized users.

Transcriptome Profiling of Primary Skin Fibroblasts Reveal Distinct Molecular Features Between PLOD1- and FKBP14-Kyphoscoliotic Ehlers–Danlos Syndrome

“…The expression of PLXNA2 is down-regulated in PLOD1 -kEDS and FKBP14 -kEDS patient fibroblasts (Figure 5H). PLXNA2 encodes the transmembrane protein plexin-A2, a member of the plexin-A family of semaphorin co-receptors, and is demonstrated to be involved in axon guidance [50]. However, nerve conduction appeared normal in FKBP14 -kEDS patients [3,4] and PLOD1 -kEDS patients [12,51].…”

Semaphorin 6A–Plexin A2/A4 Interactions with Radial Glia Regulate Migration Termination of Superficial Layer Cortical Neurons

“…Among Semas, the transmembrane-type Sema ligands Sema6A and 6B bind to the PlxnA subfamily members PlxnA2 and PlxnA4 (Suto et al., 2005, Toyofuku et al., 2008, Tawarayama et al., 2010). Their interactions regulate cell adhesion positively or negatively, depending on the situation, and contribute to the establishment of neural circuits such as corticospinal (Faulkner et al., 2008, Rünker et al., 2008) and thalamocortical projections (Leighton et al., 2001, Little et al., 2009, Mitsogiannis et al., 2017), laminar-restricted projections of hippocampal mossy fibers (Suto et al., 2005, Tawarayama et al., 2010), and laminar targeting of retinal neurons (Matsuoka et al., 2011). They also regulate cerebellar granule cell migration (Kerjan et al., 2005, Renaud et al., 2008) and interkinetic nuclear migration of retinal progenitor cells (Belle et al., 2016).…”

In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene

“…Importantly, genetic deletion of Sema6a resulted in impaired neuronal connectivity 54,55 . SEMA6A is a transmembrane protein and is known as a ligand for Plexin A2 (PLXNA2) and Plexin A4 (PLXNA4) which also play critical roles for regulating axon guidance 56 . Plxna2 and Plxna4 knockout mice showed impaired axonal development similar to those observed in mouse models with genetic deletion of Sema6a 56 .…”

“…SEMA6A is a transmembrane protein and is known as a ligand for Plexin A2 (PLXNA2) and Plexin A4 (PLXNA4) which also play critical roles for regulating axon guidance 56 . Plxna2 and Plxna4 knockout mice showed impaired axonal development similar to those observed in mouse models with genetic deletion of Sema6a 56 . Thus, dysregulation of C11orf46-mediated control of Sema6a expression may impair axonal development regulated by Plxns either in cell autonomous or non-autonomous manner, which warrants further investigation in the future.…”