Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Cell Biol. 160 (4): 481-486

Copyright © 2003 by the Rockefeller University Press.


The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response

Emma-Jane Williams1, Frank S. Walsh2, and Patrick Doherty1

1 Molecular Neurobiology Group, Medical Research Council Centre for Developmental Biology, King's College London, London SE1 1UL, UK
2 Discovery Research, Wyeth Research, Collegeville, PA 19426

Address correspondence to Patrick Doherty, Molecular Neurobiology Group, Medical Research Council Centre for Developmental Biology, King's College London, New Hunt's House, London Bridge, London SE1 1UL, UK. Tel.: 44-207-848-6813. Fax: 44-207-848-6816. E-mail: patrick.doherty{at}

Abstract: Akey role for DAG lipase activity in the control of axonal growth and guidance in vitro and in vivo has been established. For example, DAG lipase activity is required for FGF-stimulated calcium influx into neuronal growth cones, and this response is both necessary and sufficient for an axonal growth response. The mechanism that couples the hydrolysis of DAG to the calcium response is not known. The initial hydrolysis of DAG at the sn-1 position (by DAG lipase) will generate 2-arachidonylglycerol, and this molecule is well established as an endogenous cannabinoid receptor agonist in the brain. In the present paper, we show that in rat cerebellar granule neurons, CB1 cannabinoid receptor antagonists inhibit axonal growth responses stimulated by N-cadherin and FGF2. Furthermore, three CB1 receptor agonists mimic the N-cadherin/FGF2 response at a step downstream from FGF receptor activation, but upstream from calcium influx into cells. In contrast, we could find no evidence for the CB1 receptor coupling the TrkB neurotrophin receptor to an axonal growth response in the same neurons. The observation that the CB1 receptor can couple the activated FGF receptor to an axonal growth response raises novel therapeutic opportunities.

Key Words: CAM; CB1; 2-AG; cannabinoid; N-cadherin

Fascin Regulates the Migration of Subventricular Zone-Derived Neuroblasts in the Postnatal Brain.
M. Sonego, S. Gajendra, M. Parsons, Y. Ma, C. Hobbs, M. P. Zentar, G. Williams, L. M. Machesky, P. Doherty, and G. Lalli (2013)
J. Neurosci. 33, 12171-12185
   Abstract »    Full Text »    PDF »
Endocannabinoids via CB1 receptors act as neurogenic niche cues during cortical development.
J. Diaz-Alonso, M. Guzman, and I. Galve-Roperh (2012)
Phil Trans R Soc B 367, 3229-3241
   Abstract »    Full Text »    PDF »
The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling.
M. Reisenberg, P. K. Singh, G. Williams, and P. Doherty (2012)
Phil Trans R Soc B 367, 3264-3275
   Abstract »    Full Text »    PDF »
Diacylglycerol Lipase-{alpha} and -{beta} Control Neurite Outgrowth in Neuro-2a Cells through Distinct Molecular Mechanisms.
K.-M. Jung, G. Astarita, D. Thongkham, and D. Piomelli (2011)
Mol. Pharmacol. 80, 60-67
   Abstract »    Full Text »    PDF »
Genetic and pharmacologic inactivation of cannabinoid CB1 receptor inhibits angiogenesis.
S. Pisanti, P. Picardi, L. Prota, M. C. Proto, C. Laezza, P. G. McGuire, L. Morbidelli, P. Gazzerro, M. Ziche, A. Das, et al. (2011)
Blood 117, 5541-5550
   Abstract »    Full Text »    PDF »
Endocannabinoids Regulate the Migration of Subventricular Zone-Derived Neuroblasts in the Postnatal Brain.
M. J. Oudin, S. Gajendra, G. Williams, C. Hobbs, G. Lalli, and P. Doherty (2011)
J. Neurosci. 31, 4000-4011
   Abstract »    Full Text »    PDF »
Concerted Action of CB1 Cannabinoid Receptor and Deleted in Colorectal Cancer in Axon Guidance.
A. Argaw, G. Duff, N. Zabouri, B. Cecyre, N. Chaine, H. Cherif, N. Tea, B. Lutz, M. Ptito, and J.-F. Bouchard (2011)
J. Neurosci. 31, 1489-1499
   Abstract »    Full Text »    PDF »
The Cannabinoid WIN55212-2 Promotes Neural Repair After Neonatal Hypoxia-Ischemia.
D. Fernandez-Lopez, J. M. Pradillo, I. Garcia-Yebenes, J. A. Martinez-Orgado, M. A. Moro, and I. Lizasoain (2010)
Stroke 41, 2956-2964
   Abstract »    Full Text »    PDF »
Fibroblast Growth Factors in Schizophrenia.
A. F. T. van Scheltinga, S. C. Bakker, and R. S. Kahn (2010)
Schizophr Bull 36, 1157-1166
   Abstract »    Full Text »    PDF »
Differential Subcellular Recruitment of Monoacylglycerol Lipase Generates Spatial Specificity of 2-Arachidonoyl Glycerol Signaling during Axonal Pathfinding.
E. Keimpema, K. Barabas, Y. M. Morozov, G. Tortoriello, M. Torii, G. Cameron, Y. Yanagawa, M. Watanabe, K. Mackie, and T. Harkany (2010)
J. Neurosci. 30, 13992-14007
   Abstract »    Full Text »    PDF »
Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines.
I. Brown, M. G. Cascio, K. W. J. Wahle, R. Smoum, R. Mechoulam, R. A. Ross, R. G. Pertwee, and S. D. Heys (2010)
Carcinogenesis 31, 1584-1591
   Abstract »    Full Text »    PDF »
Loss of Retrograde Endocannabinoid Signaling and Reduced Adult Neurogenesis in Diacylglycerol Lipase Knock-out Mice.
Y. Gao, D. V. Vasilyev, M. B. Goncalves, F. V. Howell, C. Hobbs, M. Reisenberg, R. Shen, M.-Y. Zhang, B. W. Strassle, P. Lu, et al. (2010)
J. Neurosci. 30, 2017-2024
   Abstract »    Full Text »    PDF »
The CB1 Cannabinoid Receptor Mediates Excitotoxicity-induced Neural Progenitor Proliferation and Neurogenesis.
T. Aguado, E. Romero, K. Monory, J. Palazuelos, M. Sendtner, G. Marsicano, B. Lutz, M. Guzman, and I. Galve-Roperh (2007)
J. Biol. Chem. 282, 23892-23898
   Abstract »    Full Text »    PDF »
The Endocannabinoid System and Neurogenesis in Health and Disease.
I. Galve-Roperh, T. Aguado, J. Palazuelos, and M. Guzman (2007)
Neuroscientist 13, 109-114
   Abstract »    PDF »
A Cannabinoid Quinone Inhibits Angiogenesis by Targeting Vascular Endothelial Cells.
N. M. Kogan, C. Blazquez, L. Alvarez, R. Gallily, M. Schlesinger, M. Guzman, and R. Mechoulam (2006)
Mol. Pharmacol. 70, 51-59
   Abstract »    Full Text »    PDF »
Neural Cell Adhesion Molecule Induces Intracellular Signaling via Multiple Mechanisms of Ca2+ Homeostasis.
D. Kiryushko, I. Korshunova, V. Berezin, and E. Bock (2006)
Mol. Biol. Cell 17, 2278-2286
   Abstract »    Full Text »    PDF »
The Endocannabinoid System Promotes Astroglial Differentiation by Acting on Neural Progenitor Cells.
T. Aguado, J. Palazuelos, K. Monory, N. Stella, B. Cravatt, B. Lutz, G. Marsicano, Z. Kokaia, M. Guzman, and I. Galve-Roperh (2006)
J. Neurosci. 26, 1551-1561
   Abstract »    Full Text »    PDF »
Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor.
P. Berghuis, M. B. Dobszay, X. Wang, S. Spano, F. Ledda, K. M. Sousa, G. Schulte, P. Ernfors, K. Mackie, G. Paratcha, et al. (2005)
PNAS 102, 19115-19120
   Abstract »    Full Text »    PDF »
FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington's disease.
K. Jin, M. LaFevre-Bernt, Y. Sun, S. Chen, J. Gafni, D. Crippen, A. Logvinova, C. A. Ross, D. A. Greenberg, and L. M. Ellerby (2005)
PNAS 102, 18189-18194
   Abstract »    Full Text »    PDF »
Defective Adult Neurogenesis in CB1 Cannabinoid Receptor Knockout Mice.
K. Jin, L. Xie, S. H. Kim, S. Parmentier-Batteur, Y. Sun, X. O. Mao, J. Childs, and D. A. Greenberg (2004)
Mol. Pharmacol. 66, 204-208
   Abstract »    Full Text »    PDF »
The peripheral cannabinoid receptor Cb2, frequently expressed on AML blasts, either induces a neutrophilic differentiation block or confers abnormal migration properties in a ligand-dependent manner.
M. Alberich Jorda, N. Rayman, M. Tas, S. E. Verbakel, N. Battista, K. van Lom, B. Lowenberg, M. Maccarrone, and R. Delwel (2004)
Blood 104, 526-534
   Abstract »    Full Text »    PDF »
Polysialic Acid and Mucin Type O-Glycans on the Neural Cell Adhesion Molecule Differentially Regulate Myoblast Fusion.
M. Suzuki, K. Angata, J. Nakayama, and M. Fukuda (2003)
J. Biol. Chem. 278, 49459-49468
   Abstract »    Full Text »    PDF »
Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain.
T. Bisogno, F. Howell, G. Williams, A. Minassi, M. G. Cascio, A. Ligresti, I. Matias, A. Schiano-Moriello, P. Paul, E.-J. Williams, et al. (2003)
J. Cell Biol. 163, 463-468
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882