title: Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling.
abstract: Local environmental cues are indispensable for axonal growth and guidance during brain circuit formation. Here, we combine genetic and pharmacological tools, as well as systems neuroanatomy in human fetuses and mouse models, to study the role of endocannabinoid and Slit/Robo signalling in axonal growth. We show that excess 2-arachidonoylglycerol, an endocannabinoid affecting directional axonal growth, triggers corpus callosum enlargement due to the errant CB1 cannabinoid receptor-containing corticofugal axon spreading. This phenotype mechanistically relies on the premature differentiation and end-feet proliferation of CB2R-expressing oligodendrocytes. We further show the dependence of both axonal Robo1 positioning and oligodendroglial Slit2 production on cell-type-specific cannabinoid receptor activation. Accordingly, Robo1 and/or Slit2 manipulation limits endocannabinoid modulation of axon guidance. We conclude that endocannabinoids can configure focal Slit2/Robo1 signalling to modulate directional axonal growth, which may provide a basis for understanding impaired brain wiring associated with metabolic deficits and prenatal drug exposure.
authors.affiliation: 1] Division of Molecular Neurobiology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden [2].
authors.forename: Alán
authors.initials: A
authors.lastname: Alpár
authors.affiliation: Division of Molecular Neurobiology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tortoriello
authors.affiliation: 1] Division of Molecular Neurobiology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden [2] Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Calvigioni
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Niphakis
authors.affiliation: Institute of Neurology, Medical University of Vienna, AKH 4J, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
authors.forename: Ivan
authors.initials: I
authors.lastname: Milenkovic
authors.affiliation: Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
authors.forename: Joanne
authors.initials: J
authors.lastname: Bakker
authors.affiliation: Institute of Medical Sciences, Liquid Chromatography-Mass Spectrometry Section, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Cameron
authors.affiliation: Department of Anatomy, Histology and Embryology, Semmelweis University, Tűzoltó u. 58, H-1094 Budapest, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Hanics
authors.affiliation: Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, New York 10029, USA.
authors.forename: Claudia V
authors.initials: CV
authors.lastname: Morris
authors.affiliation: Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
authors.forename: János
authors.initials: J
authors.lastname: Fuzik
authors.affiliation: Institute of Neurology, Medical University of Vienna, AKH 4J, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
authors.affiliation: Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Cell and Developmental Biology, University College London, 21 University Street, London WC1E 6DE, UK.
authors.forename: John G
authors.initials: JG
authors.lastname: Parnavelas
authors.affiliation: Department of Cell and Developmental Biology, University College London, 21 University Street, London WC1E 6DE, UK.
authors.forename: William D
authors.initials: WD
authors.lastname: Andrews
authors.affiliation: Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, New York 10029, USA.
authors.forename: Yasmin L
authors.initials: YL
authors.lastname: Hurd
authors.affiliation: 1] Division of Molecular Neurobiology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden [2] Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria [3].
authors.forename: Erik
authors.initials: E
authors.lastname: Keimpema
authors.affiliation: 1] Division of Molecular Neurobiology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden [2] Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria [3].
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D002478:Cells, Cultured; D003337:Corpus Callosum / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D063388:Endocannabinoids / Q000494:pharmacology*; D005260:Female; D005989:Glycerides / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D043884:Receptor, Cannabinoid, CB1; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C094503:glyceryl 2-arachidonate