title: Adam22 is a major neuronal receptor for Lgi4-mediated Schwann cell signaling.
abstract: The segregation and myelination of axons in the developing PNS, results from a complex series of cellular and molecular interactions between Schwann cells and axons. Previously we identified the Lgi4 gene (leucine-rich glioma-inactivated4) as an important regulator of myelination in the PNS, and its dysfunction results in arthrogryposis as observed in claw paw mice. Lgi4 is a secreted protein and a member of a small family of proteins that are predominantly expressed in the nervous system. Their mechanism of action is unknown but may involve binding to members of the Adam (A disintegrin and metalloprotease) family of transmembrane proteins, in particular Adam22. We found that Lgi4 and Adam22 are both expressed in Schwann cells as well as in sensory neurons and that Lgi4 binds directly to Adam22 without a requirement for additional membrane associated factors. To determine whether Lgi4-Adam22 function involves a paracrine and/or an autocrine mechanism of action we performed heterotypic Schwann cell sensory neuron cultures and cell type-specific ablation of Lgi4 and Adam22 in mice. We show that Schwann cells are the principal cellular source of Lgi4 in the developing nerve and that Adam22 is required on axons. Our results thus reveal a novel paracrine signaling axis in peripheral nerve myelination in which Schwann cell secreted Lgi4 functions through binding of axonal Adam22 to drive the differentiation of Schwann cells.
authors.affiliation: Department of Cell Biology and Genetics, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands.
authors.forename: Ekim
authors.initials: E
authors.lastname: Ozkaynak
authors.forename: Gina
authors.initials: G
authors.lastname: Abello
authors.forename: Martine
authors.initials: M
authors.lastname: Jaegle
authors.forename: Laura
authors.initials: L
authors.lastname: van Berge
authors.forename: Diana
authors.initials: D
authors.lastname: Hamer
authors.forename: Linde
authors.initials: L
authors.lastname: Kegel
authors.forename: Siska
authors.initials: S
authors.lastname: Driegen
authors.forename: Koji
authors.initials: K
authors.lastname: Sagane
authors.forename: John R
authors.initials: JR
authors.lastname: Bermingham
authors.forename: Dies
authors.initials: D
authors.lastname: Meijer
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000235:genetics / Q000502:physiology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D012583:Schwann Cells / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D016326:Extracellular Matrix Proteins; C488167:LGI4 protein, human; D009419:Nerve Tissue Proteins; D051722:ADAM Proteins; C498474:ADAM22 protein, human