Eckharter Christoph, Junker Nina, Winter Lilli, Fischer Irmgard, Fogli Barbara, Kistner Steffen, Pfaller Kristian, Zheng Binhai, Wiche Gerhard, Klimaschewski Lars, Schweigreiter Rüdiger
Division of Neurobiochemistry, Biocenter, Innsbruck Medical University Innsbruck, Austria.
Max F. Perutz Laboratories, Department of Biochemistry and Cell Biology, University of Vienna Vienna, Austria.
Front Cell Neurosci. 2015 Nov 23;9:454. doi: 10.3389/fncel.2015.00454. eCollection 2015.
In contrast to the central nervous system (CNS) nerve fibers do regenerate in the peripheral nervous system (PNS) although in a clinically unsatisfying manner. A major problem is excessive sprouting of regenerating axons which results in aberrant reinnervation of target tissue and impaired functional recovery. In the CNS, the reticulon protein Nogo-A has been identified as a prominent oligodendrocyte expressed inhibitor of long-distance growth of regenerating axons. We show here that the related isoform Nogo-B is abundantly expressed in Schwann cells in the PNS. Other than Nogo-A in oligodendrocytes, Nogo-B does not localize to the myelin sheath but is detected in the ER and the plasma membrane of Schwann cells. Adult sensory neurons that are cultured on nogo-a/b deficient Schwann cells form significantly fewer axonal branches vs. those on wildtype Schwann cells, while their maximal axonal extension is unaffected. We demonstrate that this effect of Nogo-B on neuronal morphology is restricted to undifferentiated Schwann cells and is mediated by direct physical contact between these two cell types. Moreover, we show that blocking the Nogo-B specific receptor NgBR, which we find expressed on sensory neurons and to interact with Schwann cell expressed Nogo-B, produces the same branching phenotype as observed after deletion of Nogo-B. These data provide evidence for a novel function of the nogo gene that is implemented by the Nogo-B isoform. The remarkably specific effects of Nogo-B/NgBR on axonal branching, while leaving axonal extension unaffected, are of potential clinical relevance in the context of excessive axonal sprouting after peripheral nerve injury.
Nogo-B is prominently expressed in Schwann cells and localizes to the ER and plasma membrane. It distributes to the external cytoplasmic compartment of Schwann cells in vivo, but is absent from the myelin sheath.Genetic deletion of Nogo-B in Schwann cells reduces axonal branching, but not long-distance growth, of co-cultured adult sensory neurons.Schwann cell expressed Nogo-B interacts with neuronal NgBR. Blockade of NgBR mimics the loss-of-nogo branching phenotype.
与中枢神经系统（CNS）不同，周围神经系统（PNS）中的神经纤维确实会再生，尽管在临床上并不令人满意。一个主要问题是再生轴突过度发芽，这会导致靶组织的异常重新支配和功能恢复受损。在中枢神经系统中，网状蛋白Nogo - A已被确定为少突胶质细胞表达的一种突出的抑制再生轴突远距离生长的因子。我们在此表明，相关异构体Nogo - B在周围神经系统的雪旺细胞中大量表达。与少突胶质细胞中的Nogo - A不同，Nogo - B并不定位于髓鞘，而是在雪旺细胞的内质网和质膜中被检测到。与在野生型雪旺细胞上培养的成年感觉神经元相比，在缺乏nogo - a/b的雪旺细胞上培养的成年感觉神经元形成的轴突分支明显更少，而它们的最大轴突延伸不受影响。我们证明，Nogo - B对神经元形态的这种影响仅限于未分化的雪旺细胞，并且是由这两种细胞类型之间的直接物理接触介导的。此外，我们表明，阻断我们发现在感觉神经元上表达并与雪旺细胞表达的Nogo - B相互作用的Nogo - B特异性受体NgBR，会产生与删除Nogo - B后观察到的相同分支表型。这些数据为nogo基因的一种新功能提供了证据，该功能由Nogo - B异构体实现。Nogo - B/NgBR对轴突分支具有显著的特异性影响，同时不影响轴突延伸，在周围神经损伤后轴突过度发芽的情况下具有潜在的临床相关性。
Nogo - B在雪旺细胞中大量表达，定位于内质网和质膜。它在体内分布于雪旺细胞的外部细胞质区室，但髓鞘中不存在。雪旺细胞中Nogo - B的基因缺失减少了共培养的成年感觉神经元的轴突分支，但不影响其远距离生长。雪旺细胞表达的Nogo - B与神经元NgBR相互作用。阻断NgBR模拟了nogo缺失的分支表型。
