SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system
SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system
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DOI：
10.1073/pnas.0905523106
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发表时间：
2009-10-13
影响因子：
11.1
通讯作者：
Chrast, Roman
中科院分区：
文献类型：
--
作者：
Arnaud, Estelle;Zenker, Jennifer;Chrast, Roman
4C 型腓骨肌萎缩症 (CMT4C) 是一种早发、常染色体隐性遗传的脱髓鞘神经病。临床表现包括进行性脊柱侧凸、行走年龄延迟、肌肉萎缩、远端无力、神经传导速度降低。最近发现了 CMT4C 疾病的突变基因 SH3TC2/KIAA1985；然而，它编码的蛋白质的功能仍然未知。我们已经生成了敲除小鼠，其中 Sh3tc2 基因的第一个外显子被增强的 GFP 盒取代。 Sh3tc2(Delta Ex1/Delta Ex1) 基因敲除动物会出现进行性周围神经病变，表现为运动和感觉神经传导速度降低以及髓鞘形成不足。我们发现 Sh3tc2 在雪旺细胞中特异性表达，定位于质膜和核周内吞再循环室，与其在髓鞘形成和/或轴胶质相互作用区域中的可能功能一致。与此同时，对从对照和Sh3tc2(Delta Ex1/Delta Ex1)动物分离的周围神经的神经内膜室进行转录分析，发现编码参与髓鞘形成和细胞粘附的基因的转录物的变化。最后，对 Sh3tc2(Delta Ex1/Delta Ex1) 动物周围神经中致密和非致密髓磷脂结构的详细分析揭示了 Ranvier 结的异常组织，这是我们在 CMT4C 患者神经活检中证实的表型。因此，生成的 Sh3tc2 敲除小鼠提供了可靠的 CMT4C 神经病模型，该模型有助于确定 Sh3tc2 在髓鞘形成和 Ranvier 结完整性中的作用，Ranvier 结是一种可用作附加 CMT4C 诊断标记的形态表型。
Charcot-Marie-Tooth disease type 4C (CMT4C) is an early-onset, autosomal recessive form of demyelinating neuropathy. The clinical manifestations include progressive scoliosis, delayed age of walking, muscular atrophy, distal weakness, and reduced nerve conduction velocity. The gene mutated in CMT4C disease, SH3TC2/KIAA1985, was recently identified; however, the function of the protein it encodes remains unknown. We have generated knockout mice where the first exon of the Sh3tc2 gene is replaced with an enhanced GFP cassette. The Sh3tc2(Delta Ex1/Delta Ex1) knockout animals develop progressive peripheral neuropathy manifested by decreased motor and sensory nerve conduction velocity and hypomyelination. We show that Sh3tc2 is specifically expressed in Schwann cells and localizes to the plasma membrane and to the perinuclear endocytic recycling compartment, concordant with its possible function in myelination and/or in regions of axoglial interactions. Concomitantly, transcriptional profiling performed on the endoneurial compartment of peripheral nerves isolated from control and Sh3tc2(Delta Ex1/Delta Ex1) animals uncovered changes in transcripts encoding genes involved in myelination and cell adhesion. Finally, detailed analyses of the structures composed of compact and noncompact myelin in the peripheral nerve of Sh3tc2(Delta Ex1/Delta Ex1) animals revealed abnormal organization of the node of Ranvier, a phenotype that we confirmed in CMT4C patient nerve biopsies. The generated Sh3tc2 knockout mice thus present a reliable model of CMT4C neuropathy that was instrumental in establishing a role for Sh3tc2 in myelination and in the integrity of the node of Ranvier, a morphological phenotype that can be used as an additional CMT4C diagnostic marker.