Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons
Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons
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DOI：
10.1073/pnas.1212563110
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发表时间：
2013-01-29
影响因子：
11.1
通讯作者：
Harkany, Tibor
中科院分区：
文献类型：
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作者：
Keimpema, Erik;Tortoriello, Giuseppe;Harkany, Tibor
近年来，内源性大麻素，特别是2-花生四烯酸甘油(2-AG)信号已成为皮层发育过程中神经元迁移和突触形成的分子决定因素。然而，空间和时间受限的形态发生的2-AG信号的细胞类型特异性和分子调控仍未被探索。在这里，我们证明了CB1大麻素受体的遗传和药物操作永久性地改变了胆碱能投射神经元的身份和海马神经支配。我们发现，神经生长因子(NGF)参与胆碱能投射神经元的形态发生和存活，在体外通过原肌氨酸激酶A受体调节2-AG信号的分子机制，具有剂量依赖性和协调性。在此过程中，NGF将限制2-AG生物利用度的单酰甘油脂肪酶(MGL)的分选限制在近端轴突，允许CBI大麻受体上的细胞自主2-AG信号在非典型位置持续存在，从而诱导多余的轴突延伸。我们发现NGF在体外和体内都控制着MGL的降解，并发现乳腺癌1型易感蛋白(BRCA1)的E3泛素连接酶活性有助于MGL从运动性轴突片段(包括生长锥体)中清除。顺铂或基因失活BRCA1可以挽救和重新定位MGL，阻止NGF诱导的生长反应。这些数据表明，NGF可以协调内源性大麻素信号，促进胆碱能分化，并涉及BRCA1在决定神经元形态中的作用。
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.