title: EphA4 receptor shedding regulates spinal motor axon guidance.
abstract: BACKGROUND
  Proteolytic processing of axon guidance receptors modulates their expression and functions. Contact repulsion by membrane-associated ephrins and Eph receptors was proposed to be facilitated by ectodomain cleavage, but whether this phenomenon is required for axon guidance in vivo is unknown.
  
  
  RESULTS
  In support of established models, we find that cleavage of EphA4 promotes cell-cell and growth cone-cell detachment in vitro. Unexpectedly, however, a cleavage resistant isoform of EphA4 is as effective as a wild-type EphA4 in redirecting motor axons in limbs. Mice in which EphA4 cleavage is genetically abolished have motor axon guidance defects, suggesting an important role of EphA4 cleavage in nonneuronal tissues such as the limb mesenchyme target of spinal motor neurons. Indeed, we find that blocking EphA4 cleavage increases expression of full-length EphA4 in limb mesenchyme, which-via cis-attenuation-apparently reduces the effective concentration of ephrinAs capable of triggering EphA4 forward signaling in the motor axons.
  
  
  CONCLUSIONS
  We propose that EphA4 cleavage is required to establish the concentration differential of active ephrins in the target tissue that is required for proper axon guidance. Our study reveals a novel mechanism to regulate guidance decision at an intermediate target based on the modulation of ligand availability by the proteolytic processing of the receptor.
authors.affiliation: Department of Molecules-Signaling-Development, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Graziana
authors.initials: G
authors.lastname: Gatto
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morales
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B4, Canada; Division of Experimental Medicine, Department of Anatomy and Cell Biology and Department of Biology, McGill University, Montréal, QC H3A 2B2, Canada; Faculté de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
authors.forename: Artur
authors.initials: A
authors.lastname: Kania
authors.affiliation: Department of Molecules-Signaling-Development, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany. Electronic address: rklein@neuro.mpg.de.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Klein
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002448:Cell Adhesion; D036342:Ephrins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D009154:Mutation; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology*
chemical_list: D036342:Ephrins; D036122:Receptor, EphA4