Reverse signaling by Semaphorin-6A regulates cellular aggregation and neuronal morphology

Pérez-Brangulı́, Francesc; Zagar, Yvrick; Shanley, Daniel K.; Graef, Isabella A.; Chédotal, Alain; Mitchell, Kevin J.

doi:10.1101/036095

Cited by 11 publications

(22 citation statements)

References 55 publications

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“…The vertebrate class 6 semaphorins Sema6A-6D are most closely related to Drosophila Sema-1a on the basis of phylogenetic tree analyses (5). This is consistent with previous observations that vertebrate Sema6A, Sema6B, and Sema6D can mediate reverse signaling during development (12)(13)(14)(15). It remains to be determined whether the receptor functions of the closely related proteins Sema-1a and vertebrate Sema6s converge on common intracellular mediators.…”

supporting

confidence: 90%

Varicose and cheerio collaborate with pebble to mediate semaphorin-1a reverse signaling in Drosophila

Jeong

Yang

Hong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The transmembrane semaphorin Sema-1a acts as both a ligand and a receptor to regulate axon-axon repulsion during neural development. Pebble (Pbl), a Rho guanine nucleotide exchange factor, mediates Sema-1a reverse signaling through association with the N-terminal region of the Sema-1a intracellular domain (ICD), resulting in cytoskeletal reorganization. Here, we uncover two additional Sema-1a interacting proteins, varicose (Vari) and cheerio (Cher), each with neuronal functions required for motor axon pathfinding. Vari is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins, members of which can serve as scaffolds to organize signaling complexes. Cher is related to actin filament cross-linking proteins that regulate actin cytoskeleton dynamics. The PDZ domain binding motif found in the most C-terminal region of the Sema-1a ICD is necessary for interaction with Vari, but not Cher, indicative of distinct binding modalities. Pbl/Sema-1a-mediated repulsive guidance is potentiated by both and Genetic analyses further suggest that scaffolding functions of Vari and Cher play an important role in Pbl-mediated Sema-1a reverse signaling. These results define intracellular components critical for signal transduction from the Sema-1a receptor to the cytoskeleton and provide insight into mechanisms underlying semaphorin-induced localized changes in cytoskeletal organization.

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supporting

confidence: 90%

Varicose and cheerio collaborate with pebble to mediate semaphorin-1a reverse signaling in Drosophila

Jeong

Yang

Hong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…During TCA elongation in the subpallium, Sema6A, PlxnA2 and PlxnA4 are also present in several regions of the vTel, including structures, such as the corridor and the globus pallidus, suggested to play a role in directing TCA guidance during the first steps of subpallial axonal growth [21, 22, 27, 60, 61]. Combining these observations with recent evidence indicating that PlxnA2/PlxnA4–Sema6A reverse signaling occurs in vitro [36] and regulates axon guidance and targeting during murine optic system development [37], it can be hypothesized that PlxnA2 and PlxnA4 may act as a guidance cue for dLGN axons in the vTel, at the level of the IC. In this scenario, PlxnA2/PlxnA4 could provide, for instance, a repellent signal constraining axonal growth within the IC and acting specifically on Sema6A-positive dLGN projections.…”

Section: Discussionsupporting

confidence: 54%

“…In this scenario, PlxnA2/PlxnA4 could provide, for instance, a repellent signal constraining axonal growth within the IC and acting specifically on Sema6A-positive dLGN projections. At the same time, PlxnA2/PlxnA4–positive axons originating from other thalamic nuclei might be unresponsive to subpallial Sema6A due to cis PlxnA2/A4–Sema6A interactions in those thalamic axon populations [36, 38].…”

Section: Discussionmentioning

confidence: 99%

“…In the central nervous system, two Sema6A binding partners have been so far identified, Plexin-A2 (PlxnA2) and Plexin-A4 (PlxnA4). Sema6A typically acts as a ligand for PlxnA2 and PlxnA4 in the brain, but it is known to be capable of both forward and reverse signaling with the two Plexin protein family members [36, 37]. Moreover, the effects of Sema6A–PlexinAs binding are highly context-dependent, and have been shown to be modulated by association between these proteins in cis [38–41].…”

Section: Introductionmentioning

confidence: 99%

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

Mitsogiannis

Little

Mitchell

2017

Preprint

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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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“…Semaphorin signals are mediated mainly by receptors of the plexin family. In addition to acting as ligands, transmembrane semaphorins including Sema6A also serve as receptors, mediating reverse signaling (Jongbloets and Pasterkamp, 2014;Kruger et al, 2005;Perez-Branguli et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Remarkable complexity and variability of corticospinal tract defects in adult Semaphorin 6A knockout mice

et al. 2019

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The corticospinal tract (CST) has a complex and long trajectory that originates in the cerebral cortex and ends in the spinal cord. Semaphorin 6A (Sema6A), a member of the semaphorin family, is an important regulator of CST axon guidance. Previous studies have shown that postnatal Sema6A mutant mice have CST defects at the midbrain-hindbrain boundary and medulla. However, the routes the aberrant fibers take throughout the Sema6A mutant brain remain unknown. In this study, we performed 3D reconstruction of immunostained CST fibers to reevaluate the details of the abnormal CST trajectories in the brains of adult Sema6A mutant mice. Our results showed that the axon guidance defects reported in early postnatal mutants were consistently observed in adulthood. Those abnormal trajectories revealed by 3D analysis of brain sections were, however, more complex and variable than previously thought. In addition, 3D analysis allowed us to identify a few new patterns of aberrant projections. First, a subset of fibers that separated from and descended in parallel to the main bundle projected laterally at the caudal pons, subsequently changed direction by turning caudally, and extended to the medulla. Second, some abnormal fibers returned to the correct trajectory after deviating substantially from the original tract. Third, some fibers reached the pyramidal decussation normally but did not enter the dorsal funiculus. Section immunostaining combined with 3D reconstruction is a powerful method to track long projection fibers and to examine the entire nerve tracts of both normal and abnormal animals.

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Reverse signaling by Semaphorin-6A regulates cellular aggregation and neuronal morphology

Cited by 11 publications

References 55 publications

Varicose and cheerio collaborate with pebble to mediate semaphorin-1a reverse signaling in Drosophila

Varicose and cheerio collaborate with pebble to mediate semaphorin-1a reverse signaling in Drosophila

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

Remarkable complexity and variability of corticospinal tract defects in adult Semaphorin 6A knockout mice

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