PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons
PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons
复制标题
DOI：
10.1523/jneurosci.6271-09.2010
复制
发表时间：
2010-07-07
影响因子：
5.3
通讯作者：
Zochodne, Douglas W.
中科院分区：
文献类型：
--
作者：
Christie, Kimberly J.;Webber, Christine A.;Zochodne, Douglas W.
外周神经元的体内再生受到限制，很少完全，不幸的是，主要神经干横断的患者只经历有限的恢复。神经元生长信号的细胞内抑制可能是这些限制因素之一。在这项工作中，我们调查的作用，PTEN（磷酸酶和张力蛋白同源物10号染色体上删除）在周围神经元再生过程中的成年SD道利大鼠。PTEN抑制磷酸肌醇3-激酶（PI 3-K）/Akt信号传导，这是神经元生长因子下游的常见和中心的生长和存活途径。虽然PI 3-K和Akt生长信号在再生过程中在成人外周神经元内表达和激活，但PTEN类似地表达并准备抑制它们的支持。PTEN在神经元胞质、胞核、再生轴突和雪旺细胞中均有表达。体外成年感觉神经元对PTEN的分级药理学抑制和使用siRNA敲低其mRNA都有反应。这两种方法都与神经突生长的可塑性的强劲增长有关，而这种增长不依赖于mTOR（哺乳动物雷帕霉素靶蛋白）途径。重要的是，这种加速的生长是在经历了预处理损伤的神经元中产生的生长增加之外的。此外，在严重的神经横断损伤后，在损伤部位对PTEN的局部药理学抑制或对PTEN的siRNA敲低加速了体内轴突生长。研究结果表明，即使在复杂的再生环境中，通过PTEN抑制对外周神经元可塑性也有显着影响。总的来说，这些发现确定了一种新的途径来传播轴突内的内在再生途径，以利于神经修复。
In vivo regeneration of peripheral neurons is constrained and rarely complete, and unfortunately patients with major nerve trunk transections experience only limited recovery. Intracellular inhibition of neuronal growth signals may be among these constraints. In this work, we investigated the role of PTEN (phosphatase and tensin homolog deleted on chromosome 10) during regeneration of peripheral neurons in adult Sprague Dawley rats. PTEN inhibits phosphoinositide 3-kinase (PI3-K)/Akt signaling, a common and central outgrowth and survival pathway downstream of neuronal growth factors. While PI3-K and Akt outgrowth signals were expressed and activated within adult peripheral neurons during regeneration, PTEN was similarly expressed and poised to inhibit their support. PTEN was expressed in neuron perikaryal cytoplasm, nuclei, regenerating axons, and Schwann cells. Adult sensory neurons in vitro responded to both graded pharmacological inhibition of PTEN and its mRNA knockdown using siRNA. Both approaches were associated with robust rises in the plasticity of neurite outgrowth that were independent of the mTOR (mammalian target of rapamycin) pathway. Importantly, this accelerated outgrowth was in addition to the increased outgrowth generated in neurons that had undergone a preconditioning lesion. Moreover, following severe nerve transection injuries, local pharmacological inhibition of PTEN or siRNA knockdown of PTEN at the injury site accelerated axon outgrowth in vivo. The findings indicated a remarkable impact on peripheral neuron plasticity through PTEN inhibition, even within a complex regenerative milieu. Overall, these findings identify a novel route to propagate intrinsic regeneration pathways within axons to benefit nerve repair.