Endosomal sorting plays a fundamental role in directing neural development. By altering the temporal and spatial distribution of membrane receptors, endosomes regulate signaling pathways that control the differentiation and function of neural cells. Several genes linked to inherited demyelinating peripheral neuropathies, known as Charcot-Marie-Tooth (CMT) disease, encode proteins that directly interact with components of the endosomal sorting complex required for transport (ESCRT). Our previous studies demonstrated that a point mutation in the ESCRT component hepatocyte growth-factor-regulated tyrosine kinase substrate (HGS), an endosomal scaffolding protein that identifies internalized cargo to be sorted by the endosome, causes a peripheral neuropathy in the neurodevelopmentally impaired teetering mice. Here, we constructed a Schwann cell-specific deletion of Hgs to determine the role of endosomal sorting during myelination. Inactivation of HGS in Schwann cells resulted in motor and sensory deficits, slowed nerve conduction velocities, delayed myelination and hypomyelinated axons, all of which occur in demyelinating forms of CMT. Consistent with a delay in Schwann cell maturation, HGS-deficient sciatic nerves displayed increased mRNA levels for several promyelinating genes and decreased mRNA levels for genes that serve as markers of myelinating Schwann cells. Loss of HGS also altered the abundance and activation of the ERBB2/3 receptors, which are essential for Schwann cell development. We therefore hypothesize that HGS plays a critical role in endosomal sorting of the ERBB2/3 receptors during Schwann cell maturation, which further implicates endosomal dysfunction in inherited peripheral neuropathies.

SIGNIFICANCE STATEMENT Schwann cells myelinate peripheral axons, and defects in Schwann cell function cause inherited demyelinating peripheral neuropathies known as CMT. Although many CMT-linked mutations are in genes that encode putative endosomal proteins, little is known about the requirements of endosomal sorting during myelination. In this study, we demonstrate that loss of HGS disrupts the endosomal sorting pathway in Schwann cells, resulting in hypomyelination, aberrant myelin sheaths, and impairment of the ERBB2/3 receptor pathway. These findings suggest that defective endosomal trafficking of internalized cell surface receptors may be a common mechanism contributing to demyelinating CMT.

内体分选在指导神经发育中发挥着基础作用。通过改变膜受体的时间和空间分布，内体调节控制神经细胞分化和功能的信号通路。与遗传性脱髓鞘性周围神经病（称为腓骨肌萎缩症 (CMT) 病）相关的几个基因编码的蛋白质可直接与运输所需的内体分选复合物 (ESCRT) 成分相互作用。我们之前的研究表明，ESCRT 成分肝细胞生长因子调节的酪氨酸激酶底物 (HGS) 中的点突变会导致神经发育受损的摇摇欲坠的小鼠出现周围神经病变，HGS 是一种内体支架蛋白，可识别由内体分选的内化货物。在这里，我们构建了施万细胞特异性的Hgs缺失，以确定髓鞘形成过程中内体分选的作用。雪旺细胞中 HGS 失活导致运动和感觉缺陷、神经传导速度减慢、髓鞘形成延迟和轴突髓鞘形成不足，所有这些都发生在脱髓鞘形式的 CMT 中。与雪旺细胞成熟延迟一致，HGS 缺陷的坐骨神经表现出几种髓鞘形成基因的 mRNA 水平升高，而作为髓鞘形成雪旺细胞标记的基因的 mRNA 水平降低。 HGS 的缺失也改变了 ERBB2/3 受体的丰度和激活，这对于施万细胞的发育至关重要。因此，我们假设 HGS 在雪旺细胞成熟过程中 ERBB2/3 受体的内体分选中发挥关键作用，这进一步暗示遗传性周围神经病中的内体功能障碍。

意义声明雪旺细胞使周围轴突有髓鞘，雪旺细胞功能缺陷会导致遗传性脱髓鞘性周围神经病，称为 CMT。尽管许多 CMT 相关突变发生在编码假定的内体蛋白的基因中，但人们对髓鞘形成过程中内体分选的要求知之甚少。在这项研究中，我们证明 HGS 的缺失会破坏雪旺细胞中的内体分选途径，导致髓鞘形成不足、髓鞘异常以及 ERBB2/3 受体途径受损。这些发现表明，内化细胞表面受体的内体运输缺陷可能是导致脱髓鞘 CMT 的常见机制。