title: Synergistic integration of Netrin and ephrin axon guidance signals by spinal motor neurons.
abstract: During neural circuit assembly, axonal growth cones are exposed to multiple guidance signals at trajectory choice points. While axonal responses to individual guidance cues have been extensively studied, less is known about responses to combination of signals and underlying molecular mechanisms. Here, we studied the convergence of signals directing trajectory selection of spinal motor axons entering the limb. We first demonstrate that Netrin-1 attracts and repels distinct motor axon populations, according to their expression of Netrin receptors. Quantitative in vitro assays demonstrate that motor axons synergistically integrate both attractive or repulsive Netrin-1 signals together with repulsive ephrin signals. Our investigations of the mechanism of ephrin-B2 and Netrin-1 integration demonstrate that the Netrin receptor Unc5c and the ephrin receptor EphB2 can form a complex in a ligand-dependent manner and that Netrin-ephrin synergistic growth cones responses involve the potentiation of Src family kinase signaling, a common effector of both pathways.
authors.affiliation: Department of Neuroscience, Columbia University, New York, United States.|Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Poliak
authors.affiliation: Institut de recherches cliniques de Montréal, Montréal, Canada.|Integrated Program in Neuroscience, McGill University, Montréal, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morales
authors.affiliation: Institut de recherches cliniques de Montréal, Montréal, Canada.
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Croteau
authors.affiliation: Institut de recherches cliniques de Montréal, Montréal, Canada.|The Jackson Laboratory, Bar Harbor, United States.
authors.forename: Dayana
authors.initials: D
authors.lastname: Krawchuk
authors.affiliation: Institut de recherches cliniques de Montréal, Montréal, Canada.
authors.forename: Elena
authors.initials: E
authors.lastname: Palmesino
authors.affiliation: Department of Neuroscience, Columbia University, New York, United States.|Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States.|Howard Hughes Medical Institute, Columbia University, New York, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Morton
authors.affiliation: Integrated Program in Neuroscience, McGill University, Montréal, Canada.|Montréal Neurological Institute, Montréal, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Cloutier
authors.affiliation: Institut de recherches cliniques de Montréal, Montréal, Canada.|Faculté de Médecine, Université de Montréal, Montréal, Canada.|Department of Biology, McGill University, Montréal, Canada.|Department of Anatomy and Cell Biology, McGill University, Montréal, Canada.|Division of Experimental Medicine, McGill University, Montréal, Canada.
authors.forename: Frederic
authors.initials: F
authors.lastname: Charron
authors.affiliation: Department of Neuroscience, The Farber Institute for Neurosciences, Jefferson Hospital for Neuroscience, Thomas Jefferson University, Philadelphia, United States.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Dalva
authors.affiliation: The Jackson Laboratory, Bar Harbor, United States.|Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, United States.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ackerman
authors.affiliation: Institut de recherches cliniques de Montréal, Montréal, Canada.|Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan.
authors.forename: Tzu-Jen
authors.initials: TJ
authors.lastname: Kao
authors.affiliation: Institut de recherches cliniques de Montréal, Montréal, Canada.|Faculté de Médecine, Université de Montréal, Montréal, Canada.|Integrated Program in Neuroscience, McGill University, Montréal, Canada.|Department of Biology, McGill University, Montréal, Canada.|Department of Anatomy and Cell Biology, McGill University, Montréal, Canada.|Division of Experimental Medicine, McGill University, Montréal, Canada.
authors.forename: Artur
authors.initials: A
authors.lastname: Kania
mesh_terms: D000818:Animals; D036388:Ephrin-B2 / Q000378:metabolism*; D020439:Growth Cones / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D009046:Motor Neurons / Q000502:physiology*; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075386:Netrin Receptors; D000075388:Netrin-1; D036183:Receptor, EphB2 / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C000601240:EFNB2 protein, mouse; D036388:Ephrin-B2; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D017475:Receptors, Nerve Growth Factor; D025521:Tumor Suppressor Proteins; C105653:Unc5c protein, mouse; D000075388:Netrin-1; C586311:Ephb2 protein, mouse; D036183:Receptor, EphB2
keywords: Netrin; axon guidance; chicken; developmental biology; ephrin; motor neurons; mouse; neuroscience; stem cells; synergy