PTEN deletion enhances the regenerative ability of adult corticospinal neurons

作者：Kai Liu, Yi Lu, Jae K. Lee, Ramsey F. Samara, Rafer Willenberg, Ilse Sears‐Kraxberger, Andrea Tedeschi, Kevin K. Park, Duo Jin, Bin Cai, Bengang Xu, Lauren Connolly, Oswald Steward, Binhai Zheng, Zhigang He · 发表于：Nature Neuroscience · 年份：2010 · DOI：10.1038/nn.2603 · 被引用次数：1017 · 研究领域：Nerve injury and regeneration、Neurogenesis and neuroplasticity mechanisms、Spinal Cord Injury Research

The kinase mTOR functions to enhance cell growth in many systems. This study finds that injury reduces mTOR activity in neurons of the corticospinal tract (CST) and that enhancing mTOR activity by inactivation of its negative regulator PTEN substantially increases sprouting and regenerative growth of injured CST neurons. Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.