Regulation of neurite outgrowth by integrin activation
Regulation of neurite outgrowth by integrin activation
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DOI：
10.1523/jneurosci.20-17-06551.2000
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发表时间：
2000-09-01
影响因子：
5.3
通讯作者：
Lander, AD
中科院分区：
文献类型：
--
作者：
Ivins, JK;Yurchenco, PD;Lander, AD
在胚胎发育后期，视网膜神经元失去了在细胞外基质分子层粘连蛋白-1（LN-1）上附着和延伸神经突的能力，尽管它们保留了LN-1整联蛋白受体的表达。在这里，我们表明，发展损失的反应LN-1可以逆转的治疗，增加激活状态的整合素。细胞外应用Mn 2+（微摩尔浓度）和病毒介导的神经元表达的一个组成型活性形式的ras相关的GTP酶R-ras（R-ras（38 V）），有力地促进胚胎晚期视网膜神经突起生长LN-1基质。在这两种情况下，生长由整联蛋白α 6 β 1而不是α 3 β 1介导，即使这些神经元表达α 3 β 1并将其用于在其他层粘连蛋白同种型上以及在已被蛋白水解或构象活化的LN-1上的生长（Ivins等人，1998年）。Mn 2 + -和在较小程度上R-ras（38 V）-也逆转了视网膜神经元对IV型胶原蛋白的反应性的发育丧失，通过促进整合素α 1 β 1的功能。有趣的是，其他胚胎晚期CNS神经元对LN-1的反应也通过激活整合素功能的治疗而增强，但外周神经系统神经元（背根神经节神经元）的反应要么没有增强（胚胎神经元），要么只有适度改善（成年神经元）。这些结果表明，发育下降发生在神经元整合素的激活状态，特别是在中枢神经系统神经元。这种下降可能是CNS神经元在发育过程中持续的再生能力的一些内在损失的基础，并且可能是治疗干预的有效靶点。
During late-embryonic development, retinal neurons lose the ability to attach and extend neurites on the extracellular matrix molecule laminin-1 (LN-1), despite the fact that they retain expression of integrin receptors for LN-1. Here we show that the developmental loss of responsiveness to LN-1 can be reversed by treatments that increase the activation state of integrins. Both extracellular application of Mn2+ (at micromolar concentrations) and viral-mediated neuronal expression of a constitutively active form of the ras-related GTPase R-ras (R-ras (38V)) potently promoted late-embryonic retinal neurite outgrowth on LN-1 substrata. In both cases, outgrowth was mediated by integrin alpha 6 beta 1 and not alpha 3 beta 1, even though these neurons express a3b1 and use it for outgrowth on other laminin isoforms, as well as on LN-1 that has been proteolytically or conformationally activated (Ivins et al., 1998). Mn2+ -and to a much lesser extent R-ras (38V) -also reversed the developmental loss of retinal neuron responsiveness to type IV collagen, by promoting the function of integrin alpha 1 beta 1. Interestingly, the responses of other late-embryonic CNS neurons to LN-1 were also enhanced by treatments that activate integrin function, but those of peripheral nervous system neurons (dorsal root ganglion neurons) were either not enhanced (embryonic neurons) or only modestly improved (adult neurons). These results suggest that a developmental decline occurs in the activation state of neuronal integrins, particularly among CNS neurons. Such a decline may underlie some of the intrinsic loss of regenerative ability sustained by CNS neurons during development and may be a valid target for therapeutic intervention.