Selective rab11 transport and the intrinsic regenerative ability of CNS axons.
Selective rab11 transport and the intrinsic regenerative ability of CNS axons.
复制标题
选择性rab11转运和中枢神经系统轴突的内在再生能力。
DOI：
10.7554/elife.26956
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发表时间：
2017-08-08
期刊：
影响因子：
7.7
通讯作者：
Fawcett JW
中科院分区：
文献类型：
--
作者：
Koseki H;Donegá M;Lam BY;Petrova V;van Erp S;Yeo GS;Kwok JC;Ffrench-Constant C;Eva R;Fawcett JW
随着神经元的成熟，神经元失去了固有的轴突再生能力，但其机制尚不清楚。使用体外激光轴突切断术模型，我们发现切断的CNS轴突形成新的生长锥然后伸长的能力逐渐下降。再生失败与轴突切断后回缩增加有关。运输到轴突变得有选择性的成熟，我们假设，选择性排斥生长所需的分子可能有助于再生下降。随着神经元的成熟，rab11囊泡（携带许多参与轴突生长的分子）选择性地靶向体树突隔室，并通过主要的逆行运输从轴突中排除。然而，在过度表达时，rab11被错误地分配到近端轴突中，这些轴突在轴突切断后表现出较少的回缩和增强的再生。这些结果表明，内在轴突再生能力的下降与关键分子的选择性排斥有关，并且操纵运输可以增强再生。大脑和脊髓中的神经可能因创伤、中风和其他情况而受损。对这些神经纤维的损伤会破坏它们彼此之间形成的连接，这可能导致瘫痪，感觉丧失和身体控制能力丧失。如果我们能刺激受损神经纤维的再生和重新连接，那么神经功能就可以恢复。然而，尽管胚胎神经纤维在移植到成人中枢神经系统时可以再生，但随着神经纤维的成熟，这种再生能力似乎会丧失。为了研究神经纤维何时以及为什么失去再生能力，Koseki等人首先开发了一种组织培养试验，其中用激光切割单个神经纤维并成像数小时以跟踪其再生（或再生失败）。结果表明，来自中枢神经系统的神经纤维随着它们的成熟逐渐失去生长和再生的能力。为了研究为什么成熟的神经纤维不能再生，Koseki等人测量了神经纤维是否可以将生长和再生所需的一些分子运送到损伤部位。这表明，一些关键生长分子被运输的隔室被成熟的神经纤维排除在外。这些区域由一种名为rab11的蛋白质标记，Koseki等人发现，迫使rab11回到成熟的神经纤维中可以恢复它们的再生能力。在这些发现能够为患者带来新的再生治疗之前，仍然需要做很多工作，但这是向前迈出的关键一步。此外，Koseki等人开发的测定法可用于开发和测试此类治疗。
Neurons lose intrinsic axon regenerative ability with maturation, but the mechanism remains unclear. Using an in-vitro laser axotomy model, we show a progressive decline in the ability of cut CNS axons to form a new growth cone and then elongate. Failure of regeneration was associated with increased retraction after axotomy. Transportation into axons becomes selective with maturation; we hypothesized that selective exclusion of molecules needed for growth may contribute to regeneration decline. With neuronal maturity rab11 vesicles (which carry many molecules involved in axon growth) became selectively targeted to the somatodendritic compartment and excluded from axons by predominant retrograde transport However, on overexpression rab11 was mistrafficked into proximal axons, and these axons showed less retraction and enhanced regeneration after axotomy. These results suggest that the decline of intrinsic axon regenerative ability is associated with selective exclusion of key molecules, and that manipulation of transport can enhance regeneration. The nerves in the brain and spinal cord can be damaged by trauma, stroke and other conditions. Damage to these nerve fibres can destroy the connections they form with each other, which may lead to paralysis, loss of sensation and loss of body control. If we could stimulate the regeneration and reconnection of the damaged nerve fibres then neurological function could be restored. However, although embryonic nerve fibres can regenerate when they are transplanted into the adult central nervous system, this regenerative ability appears to be lost as the nerve fibres mature. To investigate when and why nerve fibres lose the ability to regenerate, Koseki et al. first developed a tissue culture assay in which individual nerve fibres were cut with a laser and imaged for several hours to track their regeneration (or failure to regenerate). The results demonstrate that nerve fibres from the central nervous system progressively lose the ability to grow and regenerate as they mature. To investigate why mature nerve fibres cannot regenerate, Koseki et al. measured whether nerve fibres can transport some of the molecules needed for growth and regeneration to sites of damage. This showed that the compartments in which some key growth molecules are transported become excluded from mature nerve fibres. These compartments are marked by a protein called rab11, and Koseki et al. found that forcing rab11 back into mature nerve fibres restored their ability to regenerate. There is still a lot of work needed before these findings can lead to a new regeneration treatment for patients, but it is a crucial step forwards. Furthermore, the assay developed by Koseki et al. could be used to develop and test such treatments.