EphB3: An endogenous mediator of adult axonal plasticity and regrowth after CNS injury
EphB3: An endogenous mediator of adult axonal plasticity and regrowth after CNS injury
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DOI：
10.1523/jneurosci.4797-05.2006
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发表时间：
2006-03-22
影响因子：
5.3
通讯作者：
Sretavan, DW
中科院分区：
文献类型：
--
作者：
Liu, X;Hawkes, E;Sretavan, DW
哺乳动物中枢神经系统损伤或疾病后神经元回路重塑的内源机制仍然主要未知。在这里，我们研究了视神经损伤后的轴突可塑性，发现巨噬细胞被募集到损伤部位和成人视网膜神经节细胞（RGC）轴突中，这些轴突经历损伤诱导的发芽和末端重塑，通过它们各自表达的在轴突引导中活跃的配体和受体对联系在一起。招募的巨噬细胞特异性上调编码引导分子 EphB3 的 mRNA，并表达能够在体内和体外结合 Ephrin B 分子的 EphB 蛋白。受伤的成年 RGC 轴突反过来表达 EphrinB3（一种已知的 EphB3 受体），并且 RGC 轴突结合注射到视神经中的重组 EphB3 蛋白。在体外，EphB3 支持成人 RGC 轴突的生长，并且轴突转向这种引导分子的来源。在体内，成年杂合动物中EphB3功能的降低和纯合动物中功能的丧失都大大减少了视神经损伤后RGC轴突的重新延伸或萌芽。 EphB3 无效和野生型同窝小鼠的轴突重新延伸的比较表明，轴突可塑性的丧失并不是由于内在轴突生长潜力的差异。相反，结果表明局部视神经来源的 EphB3 在调节视神经损伤后成人 RGC 轴突可塑性方面发挥着重要作用。值得注意的是，EphB3 的缺失并不影响受损的 RGC 轴突形成复杂末端分支的能力，这表明额外的 EphB3 独立机制控制着中枢神经系统损伤触发的成年轴突分支。
Endogenous mechanisms underlying the remodeling of neuronal circuitry after mammalian CNS injury or disease remain primarily unknown. Here, we investigated axonal plasticity after optic nerve injury and found that macrophages recruited into the injury site and adult retinal ganglion cell (RGC) axons, which undergo injury-induced sprouting and terminal remodeling, were linked by their respective expression of a ligand and receptor pair active in axon guidance. Recruited macrophages specifically upregulated mRNA encoding the guidance molecule EphB3 and expressed EphB proteins capable of binding Ephrin B molecules in vivo and in vitro. Injured adult RGC axons in turn expressed EphrinB3, a known receptor for EphB3, and RGC axons bound recombinant EphB3 protein injected into the optic nerve. In vitro, EphB3 supported adult RGC axon outgrowth, and axons turned toward a source of this guidance molecule. In vivo, both reduction of EphB3 function in adult heterozygous animals and loss of function in homozygous animals greatly decreased RGC axon re-extension or sprouting after optic nerve injury. Comparisons of axon re-extension in EphB3 null and wild-type littermates showed that this loss of axonal plasticity was not attributable to a difference in intrinsic axon growth potential. Rather, the results indicated an essential role for local optic nerve-derived EphB3 in regulating adult RGC axon plasticity after optic nerve injury. Of note, the loss of EphB3 did not affect the ability of injured RGC axons to elaborate complex terminal branching, suggesting that additional EphB3-independent mechanisms governed adult axon branching triggered by CNS damage.