Rac1 and Cdc42 but not RhoA or Rho kinase activities are required for neurite outgrowth induced by the netrin-1 receptor DCC (Deleted in Colorectal Cancer) in N1E-115 neuroblastoma cells
Rac1 and Cdc42 but not RhoA or Rho kinase activities are required for neurite outgrowth induced by the netrin-1 receptor DCC (Deleted in Colorectal Cancer) in N1E-115 neuroblastoma cells
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DOI：
10.1074/jbc.m109913200
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发表时间：
2002-04-26
影响因子：
4.8
通讯作者：
Lamarche-Vane, N
中科院分区：
文献类型：
--
作者：
Li, XD;Saint-Cyr-Proulx, E;Lamarche-Vane, N
Netrin是在发育期间吸引或排斥生长轴突的趋化性引导线索。DCC（在结直肠癌中缺失）是一种跨膜蛋白，是netrin-1的受体，参与介导这两种反应。然而，实现这一目标的机制仍不清楚。在这里，我们报告说，Rho GTP酶所需的胚胎脊髓连合轴突生长诱导netrin-1。使用N1 E-115神经母细胞瘤细胞，我们发现Rac 1和Cdc 42的活动都需要DCC诱导的神经突生长。相反，RhoA及其效应物Rho激酶的下调刺激DCC诱导神经突生长的能力。在瑞士3 T3成纤维细胞中，发现DCC通过激活Rac 1而不是Cdc 42或RhoA来触发肌动蛋白重组。我们检测到用netrin-1刺激DCC受体导致Rac 1活化增加4倍。这些结果表明，小GTP酶Rac 1，Cdc 42和RhoA作为参与神经发育过程中轴突对netrin-1反应的信号传导的重要组成部分。
Netrins are chemotropic guidance cues that attract or repel growing axons during development. DCC (deleted in colorectal cancer), a transmembrane protein that is a receptor for netrin-1, is implicated in mediating both responses. However, the mechanism by which this is achieved remains unclear. Here we report that Rho GTPases are required for embryonic spinal commissural axon outgrowth induced by netrin-1. Using N1E-115 neuroblastoma cells, we found that both Rac1 and Cdc42 activities are required for DCC-induced neurite outgrowth. In contrast, down-regulation of RhoA and its effector Rho kinase stimulates the ability of DCC to induce neurite outgrowth. In Swiss 3T3 fibroblasts, DCC was found to trigger actin reorganization through activation of Rac1 but not Cdc42 or RhoA. We detected that stimulation of DCC receptors with netrin-1 resulted in a 4-fold increase in Rac1 activation. These results implicate the small GTPases Rac1, Cdc42, and RhoA as essential components that participate in signaling the response of axons to netrin-1 during neural development.