Guirland Carmine, Suzuki Shingo, Kojima Masami, Lu Bai, Zheng James Q
Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Neuron. 2004 Apr 8;42(1):51-62. doi: 10.1016/s0896-6273(04)00157-6.
Axon guidance requires signal transduction of extracellular cues through the plasma membrane for directional motility. Here we present evidence that cholesterol- and sphingolipid-enriched membrane microdomains (lipid rafts) mediate specific guidance responses of nerve growth cones. Disruption of lipid rafts by various approaches targeting cholesterol or gangliosides selectively abolished growth cone attraction and repulsion in BDNF and netrin-1 gradients, respectively, without affecting glutamate-induced attraction. Interestingly, local raft disruption on one side of the growth cone in bath BDNF or netrin-1 produced opposite turning responses to that induced by the gradients. Raft manipulation also blocked Semaphorin 3A-induced growth cone repulsion, inhibition, and collapse. Finally, guidance responses appeared to involve raft-dependent activation of p42/p44 MAPK and ligand-induced receptor recruitment to lipid rafts. Together with the observation of asymmetric receptor-raft associations at the growth cone in guidance gradients, our findings indicate that localized signaling through membrane rafts plays a role in mediating guidance actions of extracellular cues on developing axons.
轴突导向需要细胞外信号通过质膜进行信号转导以实现定向运动。在此，我们提供证据表明，富含胆固醇和鞘脂的膜微区（脂筏）介导神经生长锥的特定导向反应。通过各种靶向胆固醇或神经节苷脂的方法破坏脂筏，分别选择性地消除了生长锥在脑源性神经营养因子（BDNF）和netrin-1梯度中的吸引和排斥，而不影响谷氨酸诱导的吸引。有趣的是，在浴槽中的BDNF或netrin-1中，生长锥一侧的局部脂筏破坏产生了与梯度诱导相反的转向反应。脂筏操纵也阻断了Semaphorin 3A诱导的生长锥排斥、抑制和塌陷。最后，导向反应似乎涉及脂筏依赖性的p42/p44丝裂原活化蛋白激酶（MAPK）激活以及配体诱导的受体募集到脂筏。连同在导向梯度中生长锥处不对称受体-脂筏关联的观察结果，我们的发现表明通过膜脂筏的局部信号传导在介导细胞外信号对发育中轴突的导向作用中发挥作用。
