Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons

Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1935-40. doi: 10.1073/pnas.1212563110. Epub 2013 Jan 14.


Endocannabinoid, particularly 2-arachidonoyl glycerol (2-AG), signaling has recently emerged as a molecular determinant of neuronal migration and synapse formation during cortical development. However, the cell type specificity and molecular regulation of spatially and temporally confined morphogenic 2-AG signals remain unexplored. Here, we demonstrate that genetic and pharmacological manipulation of CB(1) cannabinoid receptors permanently alters cholinergic projection neuron identity and hippocampal innervation. We show that nerve growth factor (NGF), implicated in the morphogenesis and survival of cholinergic projection neurons, dose-dependently and coordinately regulates the molecular machinery for 2-AG signaling via tropomyosine kinase A receptors in vitro. In doing so, NGF limits the sorting of monoacylglycerol lipase (MGL), rate limiting 2-AG bioavailability, to proximal neurites, allowing cell-autonomous 2-AG signaling at CB(1) cannabinoid receptors to persist at atypical locations to induce superfluous neurite extension. We find that NGF controls MGL degradation in vitro and in vivo and identify the E3 ubiquitin ligase activity of breast cancer type 1 susceptibility protein (BRCA1) as a candidate facilitating MGL's elimination from motile neurite segments, including growth cones. BRCA1 inactivation by cisplatin or genetically can rescue and reposition MGL, arresting NGF-induced growth responses. These data indicate that NGF can orchestrate endocannabinoid signaling to promote cholinergic differentiation and implicate BRCA1 in determining neuronal morphology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / metabolism
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Endocannabinoids / metabolism*
  • Female
  • Gene Expression Profiling
  • Glycerides / metabolism
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • Immunoblotting
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Monoacylglycerol Lipases / genetics
  • Monoacylglycerol Lipases / metabolism*
  • Nerve Growth Factor / pharmacology*
  • Neurons / drug effects*
  • Neurons / metabolism
  • PC12 Cells
  • Rats
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*


  • Arachidonic Acids
  • BRCA1 Protein
  • Endocannabinoids
  • Glycerides
  • Receptor, Cannabinoid, CB1
  • glyceryl 2-arachidonate
  • Nerve Growth Factor
  • Monoacylglycerol Lipases