The Rockefeller University, 1230, York Avenue, New York, NY, USA.
Prog Neurobiol. 2010 Jun;91(2):102-7. doi: 10.1016/j.pneurobio.2009.12.002. Epub 2009 Dec 28.
Multiple signaling pathways play key regulatory roles during the development of peripheral nervous system (PNS) and also in neuroregeneration process following nerve degeneration. Schwann cells, the glial cells of the PNS, by interacting with neuronal (axonal) ligands, mainly neuregulins via receptor tyrosine kinase (RTK) complex, ErbB2/ErbB3, initiate intracellular signaling pathways to drive proliferation and differentiation of Schwann cells, both during development and the process of regeneration and re-myelination after nerve injury. One of the major signaling kinases, extracellular signal-regulated kinase-1/2 (ERK1/2), that is also a downstream signaling pathway of neuregulin-ErbB2/ErbB3 activation, has been identified as a key regulator of Schwann cell proliferation, differentiation, demyelination and nerve regeneration. Recent studies have provided evidence that the bacterium that causes human leprosy, Mycobacterium leprae that has a unique capacity to invade Schwann cells of the adult PNS, utilizes the neuregulin-ErbB2/ErbB3 associated signaling network to the bacterial advantage. M. leprae directly bind to ErbB2 on myelinated Schwann cells and activate the RTK by a novel route that bypasses the classical neuregulin/growth factor-induced ErbB2-ErbB3 heterodimerization, and subsequently induce downstream the canonical Erk1/2 signaling, leading to myelin breakdown and subsequent axonal damage. This initial injury provides a survival advantage for M. leprae as it induces de-differentiation and generates myelin-free cells, which are highly susceptible to M. leprae invasion and promote bacterial survival. Once invaded M. leprae activate Erk1/2 via a non-canonical pathway and subsequently increase the cell proliferation and maintain the infected cells in de-differentiated state, thereby preventing remyelination. Therefore, by subverting major RTKs and signaling pathways in adult Schwann cells M. leprae appear to propagate the bacterial niche and maintain survival within the PNS. These studies may also provide new insights into our understanding of signaling mechanisms involve in both neurodegeneration and neuroregeneration.
多种信号通路在周围神经系统 (PNS) 的发育过程中以及神经变性后的神经再生过程中发挥关键的调节作用。周围神经系统的神经胶质细胞——雪旺细胞，通过与神经元（轴突）配体相互作用，主要是通过受体酪氨酸激酶 (RTK) 复合物 ErbB2/ErbB3 与神经调节蛋白结合，启动细胞内信号通路，驱动雪旺细胞的增殖和分化，无论是在发育过程中，还是在神经损伤后的再生和髓鞘再形成过程中。其中一种主要的信号激酶，细胞外信号调节激酶 1/2 (ERK1/2)，也是神经调节蛋白-ErbB2/ErbB3 激活的下游信号通路，已被确定为雪旺细胞增殖、分化、脱髓鞘和神经再生的关键调节因子。最近的研究提供了证据表明，引起人类麻风病的细菌，麻风分枝杆菌，具有独特的侵入成年 PNS 雪旺细胞的能力，利用神经调节蛋白-ErbB2/ErbB3 相关信号网络为细菌带来优势。麻风分枝杆菌直接与有髓鞘的雪旺细胞上的 ErbB2 结合，并通过一种绕过经典神经调节蛋白/生长因子诱导的 ErbB2-ErbB3 异二聚化的新途径激活 RTK，随后诱导下游典型的 Erk1/2 信号转导，导致髓鞘分解和随后的轴突损伤。这种初始损伤为麻风分枝杆菌提供了生存优势，因为它诱导去分化并产生无髓鞘细胞，这些细胞极易被麻风分枝杆菌入侵并促进细菌存活。一旦被入侵，麻风分枝杆菌通过非典型途径激活 Erk1/2，随后增加细胞增殖并使受感染的细胞保持去分化状态，从而防止髓鞘再生。因此，麻风分枝杆菌似乎通过颠覆成年雪旺细胞中的主要 RTK 和信号通路来传播细菌生境并维持其在 PNS 中的存活。这些研究也可能为我们理解涉及神经退行性变和神经再生的信号机制提供新的见解。
