Reverse Signaling by Semaphorin-6A Regulates Cellular Aggregation and Neuronal Morphology

PLoS One. 2016 Jul 8;11(7):e0158686. doi: 10.1371/journal.pone.0158686. eCollection 2016.


The transmembrane semaphorin, Sema6A, has important roles in axon guidance, cell migration and neuronal connectivity in multiple regions of the nervous system, mediated by context-dependent interactions with plexin receptors, PlxnA2 and PlxnA4. Here, we demonstrate that Sema6A can also signal cell-autonomously, in two modes, constitutively, or in response to higher-order clustering mediated by either PlxnA2-binding or chemically induced multimerisation. Sema6A activation stimulates recruitment of Abl to the cytoplasmic domain of Sema6A and phos¡phorylation of this cytoplasmic tyrosine kinase, as well as phosphorylation of additional cytoskeletal regulators. Sema6A reverse signaling affects the surface area and cellular complexity of non-neuronal cells and aggregation and neurite formation of primary neurons in vitro. Sema6A also interacts with PlxnA2 in cis, which reduces binding by PlxnA2 of Sema6A in trans but not vice versa. These experiments reveal the complex nature of Sema6A biochemical functions and the molecular logic of the context-dependent interactions between Sema6A and PlxnA2.

MeSH terms

  • Animals
  • Cell Movement / genetics
  • Cell Movement / physiology
  • Cytoplasm / metabolism
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Mice
  • Microfilament Proteins
  • NIH 3T3 Cells
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Phosphorylation / genetics
  • Phosphorylation / physiology
  • Protein Binding / genetics
  • Protein Binding / physiology
  • Protein Multimerization
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Semaphorins / genetics
  • Semaphorins / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology


  • Cytoskeletal Proteins
  • Enah protein, mouse
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Plxna2 protein, mouse
  • Receptors, Cell Surface
  • Semaphorins
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-abl

Grants and funding

This work was supported by grants from Science Foundation Ireland (07/IN.1/B969 and 09/IN.1/B2614) to KJM and by grants to Alain Chédotal from the Fondation pour la Recherche Médicale (Programme “équipe FRM”) and the LABEX LIFESENSES (reference ANR-10-LABX-65) supported by French state funds managed by the Agence National pour la Recherche within the Investissements d'Avenir programme under reference ANR-11-IDEX-0004-02.