Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Lund University, BMC A10, 22184 Lund, Sweden; Neurodegeneration and Inflammation Genetics Unit, Wallenberg Neuroscience Center, Lund University, BMC A10, 22184 Lund, Sweden.
Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC B11, 221-84 Lund, Sweden; Van Andel Research Institute, Center for Neurodegenerative Science, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA.
Neuroscience. 2014 Jan 3;256:456-66. doi: 10.1016/j.neuroscience.2013.10.029. Epub 2013 Oct 21.
Nogo-A is a transmembrane protein originally discovered in myelin, produced by postnatal CNS oligodendrocytes. Nogo-A induces growth cone collapse and inhibition of axonal growth in the injured adult CNS. In the intact CNS, Nogo-A functions as a negative regulator of growth and plasticity. Nogo-A is also expressed by certain neurons. Neuronal Nogo-A depresses long-term potentiation in the hippocampus and modulates neurite adhesion and fasciculation during development in mice. Here we show that Nogo-A is present in neurons derived from human midbrain (Lund human mesencephalic (LUHMES) cell line), as well as in embryonic and postnatal mouse midbrain (dopaminergic) neurons. In LUHMES cells, Nogo-A was upregulated threefold upon differentiation and neurite extension. Nogo-A was localized intracellularly in differentiated LUHMES cells. Cultured midbrain (dopaminergic) neurons from Nogo-A knock-out mice exhibited decreased numbers of neurites and branches when compared with neurons from wild-type (WT) mice. However, this phenotype was not observed when the cultures from WT mice were treated with an antibody neutralizing plasma membrane Nogo-A. In vivo, neither the regeneration of nigrostriatal tyrosine hydroxylase fibers, nor the survival of nigral dopaminergic neurons after partial 6-hydroxydopamine lesions was affected by Nogo-A deletion. These results indicate that during maturation of cultured midbrain (dopaminergic) neurons, intracellular Nogo-A supports neurite growth initiation and branch formation.
Nogo-A 是一种跨膜蛋白，最初在髓磷脂中发现，由出生后中枢神经系统的少突胶质细胞产生。Nogo-A 诱导损伤成年中枢神经系统中的生长锥塌陷和轴突生长抑制。在完整的中枢神经系统中，Nogo-A 作为生长和可塑性的负调节剂发挥作用。Nogo-A 也由某些神经元表达。神经元 Nogo-A 抑制海马体中的长时程增强，并在小鼠发育过程中调节神经突黏附和聚集。在这里，我们表明 Nogo-A 存在于人脑中部（Lund 人胚胎中脑（LUHMES）细胞系）衍生的神经元中，以及胚胎和出生后小鼠脑中部（多巴胺能）神经元中。在 LUHMES 细胞中，分化和神经突延伸使 Nogo-A 上调三倍。在分化的 LUHMES 细胞中，Nogo-A 定位于细胞内。与野生型（WT）小鼠的神经元相比，来自 Nogo-A 敲除小鼠的培养中脑（多巴胺能）神经元的神经突和分支数量减少。然而，当用中和质膜 Nogo-A 的抗体处理 WT 小鼠的培养物时，没有观察到这种表型。在体内，Nogo-A 缺失既不会影响黑质纹状体酪氨酸羟化酶纤维的再生，也不会影响 6-羟多巴胺损伤后黑质多巴胺能神经元的存活。这些结果表明，在培养的中脑（多巴胺能）神经元成熟过程中，细胞内 Nogo-A 支持神经突生长起始和分支形成。
