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Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling

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  • Alán Alpár

    (Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden
    Present address: Research Group of Experimental Neuroanatomy and Developmental Biology, Hungarian Academy of Sciences, Budapest, Hungary; Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary)

  • Giuseppe Tortoriello

    (Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden)

  • Daniela Calvigioni

    (Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden
    Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria)

  • Micah J. Niphakis

    (The Scripps Research Institute)

  • Ivan Milenkovic

    (Institute of Neurology, Medical University of Vienna)

  • Joanne Bakker

    (Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria)

  • Gary A. Cameron

    (Institute of Medical Sciences, Liquid Chromatography-Mass Spectrometry Section, University of Aberdeen)

  • János Hanics

    (Histology and Embryology, Semmelweis University)

  • Claudia V. Morris

    (Icahn School of Medicine at Mount Sinai)

  • János Fuzik

    (Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria)

  • Gabor G. Kovacs

    (Institute of Neurology, Medical University of Vienna)

  • Benjamin F. Cravatt

    (The Scripps Research Institute)

  • John G. Parnavelas

    (University College London)

  • William D. Andrews

    (University College London)

  • Yasmin L. Hurd

    (Icahn School of Medicine at Mount Sinai)

  • Erik Keimpema

    (Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden
    Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria)

  • Tibor Harkany

    (Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden
    Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria)

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.

Suggested Citation

  • Alán Alpár & Giuseppe Tortoriello & Daniela Calvigioni & Micah J. Niphakis & Ivan Milenkovic & Joanne Bakker & Gary A. Cameron & János Hanics & Claudia V. Morris & János Fuzik & Gabor G. Kovacs & Benj, 2014. "Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5421
    DOI: 10.1038/ncomms5421
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