Axon contact-driven Schwann cell dedifferentiation.
Axon contact-driven Schwann cell dedifferentiation.
复制标题
作者：
Soto J;Monje PV
成熟的许旺细胞（SC）在整个成年期都保持去分化的潜力。尽管如此，去分化是如何发生的仍然不确定。使用体外培养的cAMP分化和髓鞘形成SC的各种基于细胞的测定的结果揭示了背根神经节（DRG）轴突表面上表达的新的去分化活性的存在。该活性具有阻止SC分化并通过直接SC-轴突接触引起去分化的能力。提供的证据表明，即使在存在升高的cAMP的情况下，伴随着增殖的髓鞘形成SC标记物的快速损失也会发生，cAMP是驱动和维持分化状态所需的信号。去分化活性是一种膜结合蛋白，仅在DRG神经元中发现，判断其亚细胞分区，蛋白水解降解和细胞类型特异性的敏感性，并保持活跃，即使在细胞组织破坏。它不同于负责轴突接触诱导的SC增殖的膜锚定神经调节蛋白-1亚型，并且独立于从受体酪氨酸激酶和促分裂原活化蛋白激酶（如ERK和JNK）发出的促有丝分裂信号而发挥其作用。有趣的是，去分化发生时，Krox-20（一种髓鞘形成的转录增强剂）和c-Jun（一种髓鞘形成的抑制剂）的表达没有伴随变化。总之，我们的数据表明，存在细胞表面轴突来源的信号，覆盖促分化的线索，驱动去分化，并允许SC增殖响应轴突有丝分裂原。这种轴突信号可以在分化状态的开始或逆转时负调节髓鞘形成。
Mature Schwann cells (SCs) retain dedifferentiation potential throughout adulthood. Still, how dedifferentiation occurs remains uncertain. Results from a variety of cell-based assays using in vitro cultured cAMP-differentiated and myelinating SCs revealed the existence of a novel dedifferentiating activity expressed on the surface of dorsal root ganglion (DRG) axons. This activity had the capacity to prevent SC differentiation and elicit dedifferentiation through direct SC-axon contact. Evidence is provided showing that a rapid loss of myelinating SC markers concomitant to proliferation occurred even in the presence of elevated cAMP, a signal that is required to drive and maintain a differentiated state. The dedifferentiating activity was a membrane-bound protein found exclusively in DRG neurons, as judged by its subcellular partitioning, sensitivity to proteolytic degradation and cell-type specificity, and remained active even after disruption of cellular organization. It differed from the membrane-anchored neuregulin-1 isoforms that are responsible for axon contact-induced SC proliferation and exerted its action independently of mitogenic signaling emanating from receptor tyrosine kinases and mitogen-activated protein kinases such as ERK and JNK. Interestingly, dedifferentiation occurred without concomitant changes in the expression of Krox-20, a transcriptional enhancer of myelination, and c-Jun, an inhibitor of myelination. In sum, our data indicated the existence of cell surface axon-derived signals that override pro-differentiating cues, drive dedifferentiation and allow SCs to proliferate in response to axonal mitogens. This axonal signal may negatively regulate myelination at the onset or reversal of the differentiated state.