Plexins Are a Large Family of Receptors for Transmembrane, Secreted, and GPI-Anchored Semaphorins in Vertebrates

Tamagnone, Luca; Artigiani, Stefania; Chen, Hang; He, Zhigang; Guo, Ming; Song, Hong; Chédotal, Alain; Winberg, Margaret L.; Goodman, Corey S.; Poo, Mu Ming; Tessier‐Lavigne, Marc; Comoglio, Paolo M.

doi:10.1016/s0092-8674(00)80063-x

Cited by 1,054 publications

(979 citation statements)

References 39 publications

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“…[37][38][39] Plexins heterodimerize with members of the neuropilin (NRP) family to form receptors for the semaphorin family of secreted axonal chemorepellants. 40,41 Specifically, PLXNA2 heterodimerizes with either NRP1 or 2 and forms a functional receptor for the class 3 semaphorins. 40 The prevailing view is that schizophrenia is a disorder of neurodevelopment and plasticity, resulting in abnormalities of synaptic connectivity that may involve several neurotransmitters, including dopamine, glutamate and serotonin.…”

Section: Discussionmentioning

confidence: 99%

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

et al. 2006

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The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genomewide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25 000 single-nucleotide polymorphisms (SNPs) located within approximately 14 000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent casecontrol sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

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Section: Discussionmentioning

confidence: 99%

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

et al. 2006

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“…Plexins are type-I transmembrane proteins that also contain a sema domain in their extracellular part [11,12]. They are divided into four subfamilies, plexins A to D, according to the structure of their extracellular domain.…”

Section: Introductionmentioning

confidence: 99%

Poxvirus semaphorin A39R inhibits phagocytosis by dendritic cells and neutrophils

2005

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The poxvirus A39R protein is a member of the semaphorin family that binds to Plexin C1, a molecule expressed on neutrophils and dendritic cells (DC). We previously showed that binding of A39R to Plexin C1 induces local rearrangement of the actin cytoskeleton and inhibits integrin-mediated adhesion, leading to cell retraction. As phagocytosis is dependent on both cytoskeleton integrity and integrin function, we tested the effect of A39R on DC and neutrophil phagocytosis. We found that A39R treatment strongly inhibits phagocytosis by DC and neutrophils in vitro in a Plexin C1-dependent fashion. Moreover, A39R treatment inhibited the capacity of CD8a + DC to take up apoptotic bodies in vivo. As a consequence, A39R impaired the ability of CD8a + DC to cross-prime CD8 + T cells ex vivo. In contrast, A39R had no effect on direct priming of CD8 + T cells by peptide-pulsed CD8a + DC in vitro. These results suggest that poxviruses may use semaphorin homologs as a means to evade the immune system.

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“…6,7 Binding of Sema3A to NRP-1 requires the formation of a complex with PlexinA4, another member of the semaphorin family, essential for triggering intracellular signaling events. 8,9 Sema3A is mainly secreted by meningeal fibroblasts in the injured area and contributes to inadequate axonal regeneration after SCI. 3,9 Interestingly, expression of Sema3A in adult intact spinal cord is barely detectable; however, when the lesion occurs, its levels increase considerably due to breakdown of meningeal coverings, leading to migration of Sema3A-expressing fibroblasts to the lesion site and inclusion of these cells into the glial scar.…”

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confidence: 99%

“…8,9 Sema3A is mainly secreted by meningeal fibroblasts in the injured area and contributes to inadequate axonal regeneration after SCI. 3,9 Interestingly, expression of Sema3A in adult intact spinal cord is barely detectable; however, when the lesion occurs, its levels increase considerably due to breakdown of meningeal coverings, leading to migration of Sema3A-expressing fibroblasts to the lesion site and inclusion of these cells into the glial scar. 3 After SCI, descendent motor tracts and neighboring neurons express distinct components of the Sema3A signaling pathway, mainly NRP-1 and PlexinA4, which make them sensitive to Sema3A binding and inhibition of axonal regeneration.…”

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confidence: 99%

Glycan-dependent binding of galectin-1 to neuropilin-1 promotes axonal regeneration after spinal cord injury

et al. 2014

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Following spinal cord injury (SCI), semaphorin 3A (Sema3A) prevents axonal regeneration through binding to the neuropilin-1 (NRP-1)/PlexinA4 receptor complex. Here, we show that galectin-1 (Gal-1), an endogenous glycan-binding protein, selectively bound to the NRP-1/PlexinA4 receptor complex in injured neurons through a glycan-dependent mechanism, interrupts the Sema3A pathway and contributes to axonal regeneration and locomotor recovery after SCI. Although both Gal-1 and its monomeric variant contribute to de-activation of microglia, only high concentrations of wild-type Gal-1 (which co-exists in a monomer-dimer equilibrium) bind to the NRP-1/PlexinA4 receptor complex and promote axonal regeneration. Our results show that Gal-1, mainly in its dimeric form, promotes functional recovery of spinal lesions by interfering with inhibitory signals triggered by Sema3A binding to NRP-1/PlexinA4 complex, supporting the use of this lectin for the treatment of SCI patients.

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Plexins Are a Large Family of Receptors for Transmembrane, Secreted, and GPI-Anchored Semaphorins in Vertebrates

Cited by 1,054 publications

References 39 publications

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

Poxvirus semaphorin A39R inhibits phagocytosis by dendritic cells and neutrophils

Glycan-dependent binding of galectin-1 to neuropilin-1 promotes axonal regeneration after spinal cord injury

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