Differential subcellular recruitment of monoacylglycerol lipase generates spatial specificity of 2-arachidonoyl glycerol signaling during axonal pathfinding.
Endocannabinoids, particularly 2-arachidonoyl glycerol (2-AG), impact the directional turning and motility of a developing axon by activating CB(1) cannabinoid receptors (CB(1)Rs) in its growth cone. Recent findings posit that sn-1-diacylglycerol lipases (DAGLα/β) synthesize 2-AG in the motile axon segment of developing pyramidal cells. Coincident axonal targeting of CB(1)Rs and DAGLs prompts the hypothesis that autocrine 2-AG signaling facilitates axonal outgrowth. However, DAGLs alone are insufficient to account for the spatial specificity and dynamics of 2-AG signaling. Therefore, we hypothesized that local 2-AG degradation by monoacylglycerol lipase (MGL) must play a role. We determined how subcellular recruitment of MGL is temporally and spatially restricted to establish the signaling competence of 2-AG during axonal growth. MGL is expressed in central and peripheral axons of the fetal nervous system by embryonic day 12.5. MGL coexists with DAGLα and CB(1)Rs in corticofugal axons of pyramidal cells. Here, MGL and DAGLα undergo differential axonal targeting with MGL being excluded from the motile neurite tip. Thus, spatially confined MGL activity generates a 2-AG-sensing microdomain and configures 2-AG signaling to promote axonal growth. Once synaptogenesis commences, MGL disperses in stationary growth cones. The axonal polarity of MGL is maintained by differential proteasomal degradation because inhibiting the ubiquitin proteasome system also induces axonal MGL redistribution. Because MGL inactivation drives a CB(1)R-dependent axonal growth response, we conclude that 2-AG may act as a focal protrusive signal for developing neurons and whose regulated metabolism is critical for attaining correct axonal complexity.
European Neuroscience Institute at Aberdeen and Division of Applied Medicine, Aberdeen AB25 2ZD, United Kingdom.
Erik
E
Keimpema
Klaudia
K
Barabas
Yury M
YM
Morozov
Giuseppe
G
Tortoriello
Masaaki
M
Torii
Gary
G
Cameron
Yuchio
Y
Yanagawa
Masahiko
M
Watanabe
Ken
K
Mackie
Tibor
T
Harkany
D000818:Animals; D001095:Arachidonic Acids / Q000502:physiology*; D001369:Axons / Q000201:enzymology* / Q000648:ultrastructure; D015153:Blotting, Western; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D063388:Endocannabinoids; D005968:Glutamate Decarboxylase / Q000235:genetics; D005989:Glycerides / Q000502:physiology*; D007150:Immunohistochemistry; D008071:Lipoprotein Lipase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D008994:Monoacylglycerol Lipases / Q000235:genetics / Q000378:metabolism*; D009434:Neural Pathways / Q000166:cytology / Q000502:physiology; D009474:Neurons / Q000201:enzymology / Q000648:ultrastructure; D017966:Pyramidal Cells / Q000201:enzymology / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013347:Subcellular Fractions / Q000201:enzymology* / Q000648:ultrastructure; D053719:Tandem Mass Spectrometry
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; D008071:Lipoprotein Lipase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1