From the Department of Neurologic Surgery.
Medical Scientist Training Program, and.
J Biol Chem. 2013 Jul 19;288(29):20837-20842. doi: 10.1074/jbc.C113.487066. Epub 2013 Jun 17.
Negatively targeting the tumor suppressor and phosphoinositide phosphatase PTEN (phosphatase and tensin homologue) promotes axon regrowth after injury. How PTEN functions in axon guidance has remained unknown. Here we report the differential role of PTEN in chemotactic guidance of axonal growth cones. Down-regulating PTEN expression in Xenopus laevis spinal neurons selectively abolished growth cone chemorepulsion but permitted chemoattraction. These findings persisted during cAMP-dependent switching of turning behaviors. Live cell imaging using a GFP biosensor revealed rapid PTEN-dependent depression of phosphatidylinositol 3,4,5-trisphosphate levels in the growth cone induced by the repellent myelin-associated glycoprotein. Moreover, down-regulating PTEN expression blocked negative remodeling of β1-integrin adhesions triggered by myelin-associated glycoprotein, yet permitted integrin clustering by a positive chemotropic treatment. Thus, PTEN negatively regulates growth cone phosphatidylinositol 3,4,5-trisphosphate levels and mediates chemorepulsion, whereas chemoattraction is PTEN-independent. Regenerative therapies targeting PTEN may therefore suppress growth cone repulsion to soluble cues while permitting attractive guidance, an essential feature for re-forming functional neural circuits.
负向靶向肿瘤抑制因子和磷酸肌醇磷酸酶 PTEN（磷酸酶和张力蛋白同源物）可促进损伤后的轴突再生。然而，PTEN 在轴突导向中的作用仍不清楚。在这里，我们报告了 PTEN 在轴突生长锥趋化性导向中的差异作用。下调非洲爪蟾脊髓神经元中的 PTEN 表达选择性地消除了生长锥的趋化性排斥反应，但允许趋化性吸引。这些发现在 cAMP 依赖性转向行为转换期间仍然存在。使用 GFP 生物传感器的活细胞成像揭示了由排斥性髓鞘相关糖蛋白诱导的生长锥中 PTEN 依赖性的快速磷脂酰肌醇 3,4,5-三磷酸水平的抑制。此外，下调 PTEN 表达阻断了髓鞘相关糖蛋白触发的β1-整合素粘附的负性重塑，但允许整合素通过阳性趋化处理聚集。因此，PTEN 负向调节生长锥磷脂酰肌醇 3,4,5-三磷酸水平并介导趋化性排斥反应，而趋化性吸引则与 PTEN 无关。靶向 PTEN 的再生治疗方法可能因此抑制生长锥对可溶性信号的排斥反应，同时允许有吸引力的导向，这是重新形成功能性神经回路的必要特征。
