Transmembrane semaphorin5B Is Proteolytically Processed Into a Repulsive Neural Guidance Cue

J Neurochem. 2012 Oct;123(1):135-46. doi: 10.1111/j.1471-4159.2012.07885.x. Epub 2012 Aug 14.

Abstract

Developing neuronal growth cones respond to a number of post-transcriptionally modified guidance cues to establish functional neural networks. The Semaphorin family has well-established roles as both secreted and transmembrane guidance cues. Here, we describe the first evidence that a transmembrane Semaphorin, Semaphorin 5B (Sema5B), is proteolytically processed from its transmembrane form and can function as a soluble growth cone collapsing guidance cue. Over-expression of A Disintegrin and Metalloprotease (ADAM)-17, results in an enhanced release of the Sema5B ectodomain, while removal of a predicted ADAM-17 cleavage site prevents its release. In contrast, knockdown of ADAM-17 does not significantly reduce Sema5B release, indicating there are additional unknown compensating proteases. This modulation of the transmembrane Sema5B to a diffusible cue represents a sophisticated method to regulate neuronal guidance in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Animals
  • Brain / cytology
  • Brain / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Movement
  • Chick Embryo
  • Chickens
  • Coculture Techniques
  • Dimerization
  • Dipeptides / pharmacology
  • Dose-Response Relationship, Drug
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / physiology
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Growth Cones / drug effects
  • Growth Cones / physiology*
  • HEK293 Cells
  • Humans
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Mutagenesis, Site-Directed / methods
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology*
  • Neurons / drug effects
  • Organ Culture Techniques
  • Protease Inhibitors / pharmacology
  • Semaphorins / genetics
  • Semaphorins / metabolism*
  • Sequence Deletion / genetics
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / pharmacology
  • Transfection

Substances

  • Dipeptides
  • Matrix Metalloproteinase Inhibitors
  • N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide
  • Nerve Tissue Proteins
  • Protease Inhibitors
  • Semaphorins
  • Tissue Inhibitor of Metalloproteinase-1
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human