期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 5, 页码 1935-1940出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1212563110
关键词
axon guidance; basal forebrain; neurotrophin; protein stability; choline acetyltransferase
资金
- Scottish Universities Life Science Alliance
- Vetenskapsradet
- Hjarnfonden
- Novo Nordisk Foundation
- European Commission [HEALTH-F2-2007-201159]
- Karolinska Institutet
- National Institutes of Health [DA023214, DA011322, DA021696]
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 CB1 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 CBI 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据