title: Schwann Cell Expressed Nogo-B Modulates Axonal Branching of Adult Sensory Neurons Through the Nogo-B Receptor NgBR.
abstract: In contrast to the central nervous system (CNS) nerve fibers do regenerate in the peripheral nervous system (PNS) although in a clinically unsatisfying manner. A major problem is excessive sprouting of regenerating axons which results in aberrant reinnervation of target tissue and impaired functional recovery. In the CNS, the reticulon protein Nogo-A has been identified as a prominent oligodendrocyte expressed inhibitor of long-distance growth of regenerating axons. We show here that the related isoform Nogo-B is abundantly expressed in Schwann cells in the PNS. Other than Nogo-A in oligodendrocytes, Nogo-B does not localize to the myelin sheath but is detected in the ER and the plasma membrane of Schwann cells. Adult sensory neurons that are cultured on nogo-a/b deficient Schwann cells form significantly fewer axonal branches vs. those on wildtype Schwann cells, while their maximal axonal extension is unaffected. We demonstrate that this effect of Nogo-B on neuronal morphology is restricted to undifferentiated Schwann cells and is mediated by direct physical contact between these two cell types. Moreover, we show that blocking the Nogo-B specific receptor NgBR, which we find expressed on sensory neurons and to interact with Schwann cell expressed Nogo-B, produces the same branching phenotype as observed after deletion of Nogo-B. These data provide evidence for a novel function of the nogo gene that is implemented by the Nogo-B isoform. The remarkably specific effects of Nogo-B/NgBR on axonal branching, while leaving axonal extension unaffected, are of potential clinical relevance in the context of excessive axonal sprouting after peripheral nerve injury.
  
  
  RESULTS
  Nogo-B is prominently expressed in Schwann cells and localizes to the ER and plasma membrane. It distributes to the external cytoplasmic compartment of Schwann cells in vivo, but is absent from the myelin sheath.Genetic deletion of Nogo-B in Schwann cells reduces axonal branching, but not long-distance growth, of co-cultured adult sensory neurons.Schwann cell expressed Nogo-B interacts with neuronal NgBR. Blockade of NgBR mimics the loss-of-nogo branching phenotype.
authors.affiliation: Division of Neurobiochemistry, Biocenter, Innsbruck Medical University Innsbruck, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Eckharter
authors.affiliation: Division of Neurobiochemistry, Biocenter, Innsbruck Medical University Innsbruck, Austria.
authors.forename: Nina
authors.initials: N
authors.lastname: Junker
authors.affiliation: Max F. Perutz Laboratories, Department of Biochemistry and Cell Biology, University of Vienna Vienna, Austria.
authors.forename: Lilli
authors.initials: L
authors.lastname: Winter
authors.affiliation: Max F. Perutz Laboratories, Department of Biochemistry and Cell Biology, University of Vienna Vienna, Austria.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Fischer
authors.affiliation: Department of Anatomy, Histology and Embryology, Division of Neuroanatomy, Innsbruck Medical University Innsbruck, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fogli
authors.affiliation: Division of Neurobiochemistry, Biocenter, Innsbruck Medical University Innsbruck, Austria.
authors.forename: Steffen
authors.initials: S
authors.lastname: Kistner
authors.affiliation: Department of Anatomy, Histology and Embryology, Division of Histology and Embryology, Innsbruck Medical University Innsbruck, Austria.
authors.forename: Kristian
authors.initials: K
authors.lastname: Pfaller
authors.affiliation: Department of Neurosciences and Biomedical Sciences Graduate Program, School of Medicine, University of California, San Diego La Jolla, CA, USA.
authors.forename: Binhai
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Max F. Perutz Laboratories, Department of Biochemistry and Cell Biology, University of Vienna Vienna, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wiche
authors.affiliation: Department of Anatomy, Histology and Embryology, Division of Neuroanatomy, Innsbruck Medical University Innsbruck, Austria.
authors.forename: Lars
authors.initials: L
authors.lastname: Klimaschewski
authors.affiliation: Division of Neurobiochemistry, Biocenter, Innsbruck Medical University Innsbruck, Austria.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Schweigreiter
keywords: axonal branching; knockout; morphology; nogo; receptor; schwann cells; sciatic nerve; sensory neurons