The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord.
The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord.
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Rheb-mTOR 通路在受损脊髓的反应性星形胶质细胞中上调。
DOI：
10.1523/jneurosci.4103-08.2009
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发表时间：
2009-01-28
期刊：
影响因子：
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通讯作者：
Pasquale EB
中科院分区：
文献类型：
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作者：
Codeluppi S;Svensson CI;Hefferan MP;Valencia F;Silldorff MD;Oshiro M;Marsala M;Pasquale EB
中枢神经系统中的星形胶质细胞通过变得反应性来对组织损伤作出反应。它们迁移，经历肥大，并形成抑制轴突再生的胶质瘢痕。因此，限制星形胶质细胞反应代表了改善功能恢复的潜在治疗策略。最近发现，表皮生长因子（EGF）受体在星形胶质细胞损伤后上调，并促进其转化为反应性星形胶质细胞。此外，EGF受体抑制剂被证明可以增强受损视神经的轴突再生，并促进脊髓损伤后的恢复。然而，所涉及的信号转导通路尚未阐明。在这里，我们表明，在培养的成年脊髓星形胶质细胞EGF激活mTOR通路，星形胶质细胞生理学的关键调节。这是通过Akt介导的GTP酶激活蛋白Rhein的磷酸化而发生的，其抑制了Rhein抑制小GTP酶Rheb的能力。事实上，我们发现Rheb是脊髓星形胶质细胞中EGF依赖性mTOR激活所必需的，而Ras-MAP激酶通路似乎不参与其中。此外，星形胶质细胞的生长和EGF依赖的化学吸引力被mTOR选择性药物雷帕霉素抑制。我们还在脊髓损伤的缺血模型中检测到体内反应性星形胶质细胞中激活的EGF受体和mTOR信号传导水平升高。此外，Rheb表达增加可能有助于损伤脊髓中的mTOR活化。有趣的是，用雷帕霉素治疗的受伤大鼠显示出反应性胶质增生的迹象减少，这表明雷帕霉素可用于利用受损神经系统中的星形胶质细胞反应，以促进更有利于轴突再生的环境。
Astrocytes in the central nervous system respond to tissue damage by becoming reactive. They migrate, undergo hypertrophy, and form a glial scar that inhibits axon regeneration. Therefore, limiting astrocytic responses represents a potential therapeutic strategy to improve functional recovery. It was recently shown that the epidermal growth factor (EGF) receptor is upregulated in astrocytes after injury and promotes their transformation into reactive astrocytes. Furthermore, EGF receptor inhibitors were shown to enhance axon regeneration in the injured optic nerve and promote recovery after spinal cord injury. However, the signaling pathways involved were not elucidated. Here we show that in cultures of adult spinal cord astrocytes EGF activates the mTOR pathway, a key regulator of astrocyte physiology. This occurs through Akt-mediated phosphorylation of the GTPase-activating protein Tuberin, which inhibits Tuberin’s ability to inactivate the small GTPase Rheb. Indeed, we found that Rheb is required for EGF-dependent mTOR activation in spinal cord astrocytes, whereas the Ras-MAP kinase pathway does not appear to be involved. Moreover, astrocyte growth and EGF-dependent chemoattraction were inhibited by the mTOR-selective drug rapamycin. We also detected elevated levels of activated EGF receptor and mTOR signaling in reactive astrocytes in vivo in an ischemic model of spinal cord injury. Furthermore, increased Rheb expression likely contributes to mTOR activation in the injured spinal cord. Interestingly, injured rats treated with rapamycin showed reduced signs of reactive gliosis, suggesting that rapamycin could be used to harness astrocytic responses in the damaged nervous system to promote an environment more permissive to axon regeneration.