title: Signaling switch of the axon guidance receptor Robo3 during vertebrate evolution.
abstract: Development of neuronal circuits is controlled by evolutionarily conserved axon guidance molecules, including Slits, the repulsive ligands for roundabout (Robo) receptors, and Netrin-1, which mediates attraction through the DCC receptor. We discovered that the Robo3 receptor fundamentally changed its mechanism of action during mammalian evolution. Unlike other Robo receptors, mammalian Robo3 is not a high-affinity receptor for Slits because of specific substitutions in the first immunoglobulin domain. Instead, Netrin-1 selectively triggers phosphorylation of mammalian Robo3 via Src kinases. Robo3 does not bind Netrin-1 directly but interacts with DCC. Netrin-1 fails to attract pontine neurons lacking Robo3, and attraction can be restored in Robo3(-/-) mice by expression of mammalian, but not nonmammalian, Robo3. We propose that Robo3 evolution was key to sculpting the mammalian brain by converting a receptor for Slit repulsion into one that both silences Slit repulsion and potentiates Netrin attraction.
authors.affiliation: INSERM, UMRS U968, Institut de la Vision, Paris 75012, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Univ Paris 06, Institut de la Vision, Paris 75012, France; CNRS, UMR 7210, Paris 75012, France.
authors.forename: Pavol
authors.initials: P
authors.lastname: Zelina
authors.affiliation: INSERM, UMRS U968, Institut de la Vision, Paris 75012, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Univ Paris 06, Institut de la Vision, Paris 75012, France; CNRS, UMR 7210, Paris 75012, France.
authors.forename: Heike
authors.initials: H
authors.lastname: Blockus
authors.affiliation: INSERM, UMRS U968, Institut de la Vision, Paris 75012, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Univ Paris 06, Institut de la Vision, Paris 75012, France; CNRS, UMR 7210, Paris 75012, France.
authors.forename: Yvrick
authors.initials: Y
authors.lastname: Zagar
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris 75005, France; CNRS, UMR 8197, Paris 75005, France; INSERM, U1024, Paris 75005, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Péres
authors.affiliation: INSERM, UMRS U968, Institut de la Vision, Paris 75012, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Univ Paris 06, Institut de la Vision, Paris 75012, France; CNRS, UMR 7210, Paris 75012, France.
authors.forename: François
authors.initials: F
authors.lastname: Friocourt
authors.affiliation: The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Zhuhao
authors.initials: Z
authors.lastname: Wu
authors.affiliation: INSERM, UMRS U968, Institut de la Vision, Paris 75012, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Univ Paris 06, Institut de la Vision, Paris 75012, France; CNRS, UMR 7210, Paris 75012, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Rama
authors.affiliation: CNRS, UMR 7102, Paris 75005, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Fouquet
authors.affiliation: Imperial College London, Department of Life Sciences, London SW7 2AZ, UK.
authors.forename: Erhard
authors.initials: E
authors.lastname: Hohenester
authors.affiliation: The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.affiliation: Institute Biology I, University of Freiburg, Freiburg 79104, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Schweitzer
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris 75005, France; CNRS, UMR 8197, Paris 75005, France; INSERM, U1024, Paris 75005, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Roest Crollius
authors.affiliation: INSERM, UMRS U968, Institut de la Vision, Paris 75012, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Univ Paris 06, Institut de la Vision, Paris 75012, France; CNRS, UMR 7210, Paris 75012, France. Electronic address: alain.chedotal@inserm.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Chédotal
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D005075:Biological Evolution; D002465:Cell Movement; D000075389:DCC Receptor; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000075388:Netrin-1; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015027:Zebrafish; D019061:src-Family Kinases / Q000378:metabolism; D000097905:Roundabout Proteins
chemical_list: D000075389:DCC Receptor; D006023:Glycoproteins; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075388:Netrin-1; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D019061:src-Family Kinases; C501910:Dcc protein, mouse; C000617351:NTN1 protein, human; C000617353:Ntn1 protein, mouse; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C120566:slit protein, vertebrate