Lin Weichun, Dominguez Bertha, Yang Jiefei, Aryal Prafulla, Brandon Eugene P, Gage Fred H, Lee Kuo-Fen
The Salk Institute, La Jolla, California 92037, USA.
Neuron. 2005 May 19;46(4):569-79. doi: 10.1016/j.neuron.2005.04.002.
Synapse formation requires interactions between pre- and postsynaptic cells to establish the connection of a presynaptic nerve terminal with the neurotransmitter receptor-rich postsynaptic apparatus. At developing vertebrate neuromuscular junctions, acetylcholine receptor (AChR) clusters of nascent postsynaptic apparatus are not apposed by presynaptic nerve terminals. Two opposing activities subsequently promote the formation of synapses: positive signals stabilize the innervated AChR clusters, whereas negative signals disperse those that are not innervated. Although the nerve-derived protein agrin has been suggested to be a positive signal, the negative signals remain elusive. Here, we show that cyclin-dependent kinase 5 (Cdk5) is activated by ACh agonists and is required for the ACh agonist-induced dispersion of the AChR clusters that have not been stabilized by agrin. Genetic elimination of Cdk5 or blocking ACh production prevents the dispersion of AChR clusters in agrin mutants. Therefore, we propose that ACh negatively regulates neuromuscular synapse formation through a Cdk5-dependent mechanism.
突触形成需要突触前和突触后细胞之间的相互作用，以建立突触前神经末梢与富含神经递质受体的突触后装置的连接。在发育中的脊椎动物神经肌肉接头处，新生突触后装置的乙酰胆碱受体（AChR）簇并未与突触前神经末梢相对。随后，两种相反的活动促进了突触的形成：正向信号稳定受神经支配的AChR簇，而负向信号则驱散未受神经支配的AChR簇。尽管神经源性蛋白聚集蛋白被认为是一种正向信号，但负向信号仍然难以捉摸。在这里，我们表明细胞周期蛋白依赖性激酶5（Cdk5）被ACh激动剂激活，并且是ACh激动剂诱导未被聚集蛋白稳定的AChR簇分散所必需的。Cdk5的基因消除或ACh产生的阻断可防止聚集蛋白突变体中AChR簇的分散。因此，我们提出ACh通过Cdk5依赖性机制负向调节神经肌肉突触的形成。
