NGF enhances sensory axon growth induced by laminin but not by the L1 cell adhesion molecule
NGF enhances sensory axon growth induced by laminin but not by the L1 cell adhesion molecule
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DOI：
10.1006/mcne.2002.1107
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发表时间：
2002-05-01
影响因子：
3.5
通讯作者：
Maness, PF
中科院分区：
文献类型：
--
作者：
Liu, RY;Schmid, RS;Maness, PF
神经营养因子和细胞粘附分子调节轴突的引导，但它们之间潜在的协调相互作用尚未明确。特别是，由于胚胎神经元的生存强烈依赖于这类分子，因此很难确定来自不同表面分子的信号在神经营养因子诱导的轴突生长中的作用。我们已经用Bax缺陷神经元解决了这个问题，这种神经元不需要神经营养素来维持生存。L1神经细胞粘附分子和层粘连蛋白分别支持胚胎Bax（-/-）小鼠背根神经节感觉神经元不依赖ngf的轴突生长。然而，神经生长因子（NGF）在层粘连蛋白上刺激感觉神经元额外的轴突生长，而在L1底物上则没有。显性阴性突变体RhoA（T19N）抑制小GTPase RhoA，恢复了L1对Bax（-/-）神经元轴突生长的NGF反应性。组成型激活的RhoA（Q63L）不影响L1上轴突的生长，但抑制ngf刺激的层粘连蛋白上轴突的生长。RhoA抑制剂O21N-C3毒素刺激NGF野生型DRG神经元L1轴突生长，与层粘连蛋白上的RhoA被NGF下调而L1上的RhoA不被NGF下调的概念一致。这些结果表明，RhoA GTPase介导了ngf诱导的胚胎感觉轴突生长的一种新的底物依赖性调节。
Neurotrophins and cell adhesion molecules regulate axon guidance, but their potential coordinate interactions are not well defined. In particular, it has been difficult to define the role of signaling from different surface molecules in neurotrophin-induced axon growth because of the strong dependence of embryonic neurons on this class of molecules for survival. We have addressed this issue using Bax deficient neurons, which do not require neurotrophins for survival. The L1 neural cell adhesion molecule and laminin each supported NGF-independent axon growth of cultured sensory neurons from dorsal root ganglia of embryonic Bax(-/-) mice. However, nerve growth factor (NGF) stimulated additional axon growth of sensory neurons on laminin but not on L1 substrates. Inhibition of the small GTPase RhoA by the dominant-negative mutant RhoA(T19N) restored NGF responsiveness of axon growth on L1 to Bax(-/-) neurons. Constitutively activated RhoA(Q63L) did not affect axon growth on L1 but inhibited NGF-stimulated axon growth on laminin. Consistent with the concept that RhoA was downregulated by NGF in neurons on laminin but not L1, the RhoA inhibitor O21N-C3 toxin stimulated axon growth on L1 in wild-type DRG neurons in NGF. These results demonstrate a novel substrate-dependent regulation of NGF-induced growth of embryonic sensory axons mediated by RhoA GTPase.