The Role of ESCRTs in Regulating Nervous System Function

在美国，周围神经疾病影响着2000多万人。患有外周疾病的患者 神经病患有衰弱的运动和感觉障碍，可能会导致严重的疼痛和瘫痪。 许多形式的遗传性周围神经病损害雪旺细胞功能并导致髓鞘异常 生产或脱髓鞘，这被认为是运动和感觉缺陷的根本原因。 雪旺细胞与轴突紧密结合，在发育过程中组织周围神经，并 用髓鞘隔离轴突。NRG1/ERBB信号通路允许雪旺细胞和轴突 相互交流，并提供调控雪旺细胞增殖的基本指令， 迁移和髓鞘形成。调节NRG1/ERBB信号通路可以恢复几个 Charcot-Marie-Tooth病(CMT)啮齿动物模型因此，确定控制 NRG1/ERBB信号转导通路对周围神经病的治疗具有重要意义。我们的数据来自 小鼠和细胞培养实验表明，内小体是ERBB2/3功能的关键调节因子 髓鞘形成。为了研究控制ERBB2/3信号的内体通路，我们培育了小鼠 损害内化细胞表面受体的内体分选的模型。我们一直专注于肝细胞 生长因子调节的酪氨酸激酶底物(HGS)，指导内化受体的分选 通过内生体。HGS在两种不同的CMT小鼠模型中表达减弱，提示 脱髓鞘神经病的原因之一是有缺陷的内体分选。我们的数据现在表明， 雪旺细胞中的HGS复制了遗传性周围神经疾病的许多特征，包括运动和 坐骨神经感觉障碍和髓鞘障碍。HGS基因缺失导致内体功能受损 具体地说，在雪旺细胞中也表明ERBB2/3受体的信号转导依赖于内体 分选以激活其下游信号通路。此外，我们还鉴定了一种新的内噬菌体 雪旺细胞中的蛋白质复合体，发生在髓鞘形成过程中。来检验内体分选的假说 调节髓鞘形成过程中的ERBB2/3功能，Aim 1将决定内体分选在Schwann中的作用 外周神经发育和功能的细胞，以及目标2将决定内吞如何运输 控制雪旺细胞中ERBB2/3受体的分选和信号传递。探讨其作用机制 调节雪旺细胞中ERBB2/3的功能，Aim 3将决定哪些HGS相互作用蛋白复合体 是雪旺细胞中ERBB2/3分选和信号传递所必需的。这项提案有望完成。 为雪旺细胞的内体生物学提供新的见解，并加深我们对 在髓鞘形成过程中，内体分选控制ERBB受体信号。我们的长期目标是确定 控制雪旺细胞内小体功能以识别靶的调节通路 治疗脱髓鞘疾病，如CMT。

Peripheral neuropathies affect more than 20 million people in the United States. Patients with peripheral neuropathies suffer from debilitating motor and sensory deficits that can cause severe pain and paralysis. Many forms of inherited peripheral neuropathies impair Schwann cell function and result in abnormal myelin production or demyelination, which is thought to be the underlying cause of the motor and sensory deficits. Schwann cells intimately associate with axons to organize peripheral nerves during development and to insulate axons with myelin. The NRG1/ERBB signaling pathway allows for Schwann cells and axons to communicate with each other and provides essential instructions that regulate Schwann cell proliferation, migration and myelination. Modulation of the NRG1/ERBB signaling pathway can restore function to several rodent models of Charcot-Marie-Tooth disease (CMT). Therefore, identifying the mechanisms that control NRG1/ERBB signaling has important implications for the treatment of peripheral neuropathies. Our data from mice and cell culture experiments indicate that the endosome is a critical regulator of ERBB2/3 function during myelination. To investigate the endosomal pathways controlling ERBB2/3 signaling, we have developed mouse models that impair endosomal sorting of internalized cell surface receptors. We have focused on hepatocyte growth factor regulated tyrosine kinase substrate (HGS), which directs the sorting of internalized receptors through the endosome. HGS expression is diminished in two different mouse models of CMT, implicating defective endosomal sorting as a cause for demyelinating neuropathies. Our data now indicate that loss of HGS in Schwann cells replicates many features of inherited peripheral nerve disorders, including motor and sensory deficits and dysmyelination of sciatic nerves. Impairing endosomal function by deleting the Hgs gene specifically in Schwann cells also showed that ERBB2/3 receptor signaling is dependent upon endosomal sorting to activate its downstream signaling pathways. In addition, we have identified a novel endosomal protein complex in Schwann cells that occurs during myelination. To test the hypothesis that endosomal sorting regulates ERBB2/3 function during myelination, Aim 1 will determine the role of endosomal sorting in Schwann cells for the development and function of peripheral nerves, and Aim 2 will determine how endocytic trafficking controls the sorting and signaling of the ERBB2/3 receptors in Schwann cells. To investigate the mechanism regulating ERBB2/3 function in Schwann cells, Aim 3 will determine which HGS interacting protein complexes are required for ERBB2/3 sorting and signaling in Schwann cells. The completion of this proposal is expected to provide novel insights on the endosomal biology of Schwann cells and further our understanding of how endosomal sorting controls ERBB receptor signaling during myelination. Our long-range goals are to determine the regulatory pathways that control endosomal function in Schwann cells in order to identify targets for the treatment of demyelinating diseases such as CMT.