title: Operational redundancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2.
abstract: Axon pathfinding is orchestrated by numerous guidance cues, including Slits and their Robo receptors, but it remains unclear how information from multiple cues is integrated or filtered. Robo3, a Robo family member, allows commissural axons to reach and cross the spinal cord midline by antagonizing Robo1/2-mediated repulsion from midline-expressed Slits and potentiating deleted in colorectal cancer (DCC)-mediated midline attraction to Netrin-1, but without binding either Slits or Netrins. We identified a secreted Robo3 ligand, neural epidermal growth factor-like-like 2 (NELL2), which repels mouse commissural axons through Robo3 and helps steer them to the midline. These findings identify NELL2 as an axon guidance cue and establish Robo3 as a multifunctional regulator of pathfinding that simultaneously mediates NELL2 repulsion, inhibits Slit repulsion, and facilitates Netrin attraction to achieve a common guidance purpose.
authors.affiliation: Division of Research, Genentech, South San Francisco, CA 94080, USA. Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA. Department of Neuroscience, Brown University, Providence, RI 02912, USA. alexander_jaworski@brown.edu marctl@rockefeller.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jaworski
authors.affiliation: Department of Protein Chemistry, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Tom
authors.affiliation: Department of Protein Chemistry, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Raymond K
authors.initials: RK
authors.lastname: Tong
authors.affiliation: Department of Neuroscience, Brown University, Providence, RI 02912, USA.
authors.forename: Holly K
authors.initials: HK
authors.lastname: Gildea
authors.affiliation: Department of Protein Chemistry, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Koch
authors.affiliation: Department of Protein Chemistry, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Lino C
authors.initials: LC
authors.lastname: Gonzalez
authors.affiliation: Division of Research, Genentech, South San Francisco, CA 94080, USA. Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA. alexander_jaworski@brown.edu marctl@rockefeller.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000075388:Netrin-1; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000378:metabolism; D013116:Spinal Cord / Q000196:embryology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000097905:Roundabout Proteins
chemical_list: D008024:Ligands; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075388:Netrin-1; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D025521:Tumor Suppressor Proteins; D000097905:Roundabout Proteins; C491253:Nell2 protein, mouse; C000617353:Ntn1 protein, mouse; C498888:Robo2 protein, mouse; C118348:Robo3 protein, mouse; C120010:Slit1 protein, mouse