Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling

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, Benjamin F Cravatt, John G Parnavelas, William D Andrews, Yasmin L Hurd, Erik Keimpema, Tibor Harkany

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Article number4421
Pages (from-to)1-13
Number of pages13
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 17 Jul 2014

Keywords

  • Cell signalling
  • Development of the nervous system
  • Neuronal physiology
  • Receptor, Cannabinoid, CB1
  • Endocannabinoids

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    Alpár, A., Tortoriello, G., Calvigioni, D., Niphakis, M. J., Milenkovic, I., Bakker, J., Cameron, G. A., Hanics, J., Morris, C. V., Fuzik, J., Kovacs, G. G., Cravatt, B. F., Parnavelas, J. G., Andrews, W. D., Hurd, Y. L., Keimpema, E., & Harkany, T. (2014). Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling. Nature Communications, 5, 1-13. [4421]. https://doi.org/10.1038/ncomms5421