title: Concerted action of CB1 cannabinoid receptor and deleted in colorectal cancer in axon guidance.
abstract: Endocannabinoids (eCBs) are retrograde neurotransmitters that modulate the function of many types of synapses. The presence of eCBs, their CB1 receptor (CB1R), and metabolizing enzymes at embryonic and early postnatal periods have been linked to developmental processes such as neuronal proliferation, differentiation, and migration, axon guidance, and synaptogenesis. Here, we demonstrate the presence of a functional eCB system in the developing visual system and the role of CB1R during axon growth and retinothalamic development. Pharmacological treatment of retinal explants and primary cortical neuron cultures with ACEA, a selective CB1R agonist, induced a collapse of the growth cone (GC). Furthermore the application of AM251, a CB1R inverse agonist, to the neuronal cultures increased the surface area of GC. In vivo, intraocular injection of ACEA diminished retinal projection growth, while AM251 promoted growth and caused aberrant projections. In addition, compared with their wild-type littermates, CB1R-deficient adult mice revealed a lower level of eye-specific segregation of retinal projections in the dorsal lateral geniculate nucleus. Finally, we found that pharmacological modulation of CB1R affected the trafficking of Deleted in colorectal cancer (DCC) receptor to the plasma membrane in a PKA-dependent manner. Moreover, pharmacological inhibition or genetic inactivation of DCC abolished the CB1R-induced reorganization of the GC. Overall, these findings establish a mechanism by which the CB1R influences GC behavior and nervous system development in concerted action with DCC.
authors.affiliation: University of Montreal, Montreal, Quebec H3T 1J4, Canada.
authors.forename: Anteneh
authors.initials: A
authors.lastname: Argaw
authors.forename: Gabriel
authors.initials: G
authors.lastname: Duff
authors.forename: Nawal
authors.initials: N
authors.lastname: Zabouri
authors.forename: Bruno
authors.initials: B
authors.lastname: Cécyre
authors.forename: Natacha
authors.initials: N
authors.lastname: Chainé
authors.forename: Hosni
authors.initials: H
authors.lastname: Cherif
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tea
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Maurice
authors.initials: M
authors.lastname: Ptito
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bouchard
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D000075389:DCC Receptor; D054314:Drug Inverse Agonism; D020439:Growth Cones / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D021381:Protein Transport; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D012160:Retina / Q000196:embryology / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000648:ultrastructure; D013788:Thalamus / Q000196:embryology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D063385:Cannabinoid Receptor Modulators; D000075389:DCC Receptor; C501910:Dcc protein, mouse; D018377:Neurotransmitter Agents; D043884:Receptor, Cannabinoid, CB1; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases