Regulation of Schwann cell enshealthment and myelination by type III Neuregulin 1

本研究计划的长期目标是阐明轴突如何驱动雪旺细胞鞘鞘和髓鞘形成。我们正在研究神经调节蛋白-1 （NRG1）的作用，NRG1是一种神经生长因子，它调节整个雪旺细胞谱系，包括PNS中鞘鞘和髓鞘形成之间的二元选择。III型NRG1驱动雪旺细胞鞘鞘和髓鞘形成的机制尚不清楚。NRG1与雪旺细胞上的erbB受体结合，激活PI 3激酶、PLC-3和MAP激酶信号通路。我们的一般模型是，雪旺细胞的存活、成鞘和髓鞘包裹都需要依赖nrg1的PI 3激酶激活，而其他信号通路可能驱动髓鞘特异性转录因子（TFs）的顺序表达。使用最近生成的表达激活的、膜靶向形式的Akt1的转基因小鼠，我们将进一步研究NRG1如何驱动轴突鞘鞘、髓鞘形成和存活。具体而言，我们将：i)通过分析Akt亚型缺失的小鼠，并通过在雪旺细胞中表达活化的Akt与NRG1缺失的神经元相互作用，研究Akt是否为PI 3-激酶依赖性存活和鞘鞘形成的主要效应因子；ii)表征TORC1和TORC2通路在鞘鞘形成和髓鞘形成中的作用；iii)分析Akt是否与其他信号（包括NFAT）在髓鞘形成过程中协同作用。通过交叉表达活化的Akt和NFAT转基因小鼠，并研究潜在的髓鞘形成协同效应。这些研究将为了解轴突上的III型NRG1如何驱动雪旺细胞的存活、鞘鞘和髓鞘形成提供重要的见解。相关性：这些研究试图识别促进髓鞘形成的信号，髓鞘是包围神经纤维的细胞绝缘，对其正常功能和长期完整性至关重要。因此，本研究的发现可能对髓鞘纤维疾病（包括神经病变）的发病机制具有重要意义，并导致新的治疗策略来促进其修复。

The long term goal of this research program is to elucidate how axons drive Schwann cell ensheathment and myelination. We are investigating the role of neuregulin-1 (NRG1), a neuronal growth factor which regulates the entire Schwann cell lineage, including the binary choice between ensheathment and myelination in the PNS. The mechanisms by which type III NRG1 drives Schwann cell ensheathment and myelination remain poorly understood. NRG1 binds to erbB receptors on Schwann cells, activating the PI 3-kinase, PLC-3, and MAP kinase signaling pathways. Our general model is that Schwann cell survival, ensheathment and myelin wrapping all require NRG1-dependent activation of PI 3-kinase whereas other signaling pathways may drive the sequential expression of myelin-specific transcription factors (TFs). Using a recently generated transgenic mouse that expresses an activated, membrane targeted form of Akt1, we will investigate further how NRG1 drives axon ensheathment, myelination, and survival. Specifically, we will: i) investigate whether Akt is a primary effector of PI 3-kinase- dependent survival and ensheathment by analyzing mice deficient in Akt isoforms and by expressing activated Akt in Schwann cells interacting with NRG1 deficient neurons, ii) characterize the role(s) of the TORC1 and TORC2 pathways in ensheathment and myelination, and iii) analyze whether Akt cooperates with other signals, including NFAT, during myelination, by crossing transgenic mice expressing activated Akt and NFAT transgenes and examine potential cooperative effects on myelination. These studies should provide important insights into how type III NRG1 on the axon drives survival, ensheathment and myelination by Schwann cells. Relevance: These studies seek to identify signals that promote myelin sheath formation, the cellular insulation that surrounds nerve fibers and is critical for their proper function and long term integrity. Findings in this study may therefore have important implications for the pathogenesis of disorders of myelinated fibers, including neuropathies, and lead to new therapeutic strategies to promote their repair.