title: Reverse Signaling by Semaphorin-6A Regulates Cellular Aggregation and Neuronal Morphology.
abstract: 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.
authors.affiliation: Smurfit Institute of Genetics and Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Francesc
authors.initials: F
authors.lastname: Perez-Branguli
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S968, CNRS_UMR7210, Institut de la Vision, Paris, France.
authors.forename: Yvrick
authors.initials: Y
authors.lastname: Zagar
authors.affiliation: Smurfit Institute of Genetics and Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Shanley
authors.affiliation: Department of Pathology, Stanford University Medical School, Stanford, California, United States of America.
authors.forename: Isabella A
authors.initials: IA
authors.lastname: Graef
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S968, CNRS_UMR7210, Institut de la Vision, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Chédotal
authors.affiliation: Smurfit Institute of Genetics and Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D055503:Protein Multimerization; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D003598:Cytoskeletal Proteins; C102176:Enah protein, mouse; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C492113:Plxna2 protein, mouse; D011956:Receptors, Cell Surface; D039961:Semaphorins; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl