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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.

SUBMITTER: Alpar A

PROVIDER: S-EPMC4110686 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling.

Alpár Alán A Tortoriello Giuseppe G Calvigioni Daniela D Niphakis Micah J MJ Milenkovic Ivan I Bakker Joanne J Cameron Gary A GA Hanics János J Morris Claudia V CV Fuzik János J Kovacs Gabor G GG Cravatt Benjamin F BF Parnavelas John G JG Andrews William D WD Hurd Yasmin L YL Keimpema Erik E Harkany Tibor T

Nature communications 20140717

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 cort ...[more]

PMID: 25030704

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Project description:AimsPrevious reports indicated that the Slit2-Robo signalling pathway is involved in embryonic heart development and fibrosis in other solid organs, but its function in adult cardiac fibrosis has not been investigated. Here, we investigate the role of the Slit2-Robo1 signalling pathway in cardiac fibrosis.Methods and resultsThe right atrial tissue samples were obtained from patients with valvular heart disease complicated by atrial fibrillation during heart valve surgery and from healthy heart donors. The fibrotic animal model is created by performing transverse aortic constriction (TAC) surgery. The Robo1, Slit2, TGF-?1, and collagen I expression levels in human and animal samples were evaluated by immunohistochemistry and western blot analysis. Echocardiography measured the changes in heart size and cardiac functions of animals. Angiotensin II (Ang II), Slit2-siRNA, TGF-?1-siRNA, recombinant Slit2, and recombinant TGF-?1 were transfected to cardiac fibroblasts (CFs) respectively to observe their effects on collagen I expression level. The right atrial appendage of patients with valvular heart disease complicated by atrial fibrillation found significantly up-regulated Slit2, Robo1, TGF-?1, and collagen I expression levels. TAC surgery leads to heart enlargement, cardiac fibrosis, and up-regulation of Slit2, Robo1, TGF-?1, and collagen I expression levels in animal model. Robo1 antagonist R5 and TGF-?1 antagonist SB431542 suppressed cardiac fibrosis in TAC mice. Treatment with 100 nM Ang II in CFs caused significantly increased Slit2, Robo1, Smad2/3, TGF-?1, collagen I, PI3K, and Akt expression levels. Transfecting Slit2-siRNA and TGF-?1-siRNA, respectively, into rat CFs significantly down-regulated Smad2/3 and collagen I expression, inhibiting the effects of Ang II. Recombinant Slit2 activated the TGF-?1/Smad signalling pathway in CFs and up-regulated Periostin, Robo1, and collagen I expression.ConclusionsThe Slit2-Robo1 signalling pathway interfered with the TGF-?1/Smad pathway and promoted cardiac fibrosis. Blockade of Slit2-Robo1 might be a new treatment for cardiac fibrosis.

Dataset Information

Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling.

Publications

Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling.

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