Giant ankyrin-G: A critical innovation in vertebrate evolution of fast and integrated neuronal signaling
Giant ankyrin-G: A critical innovation in vertebrate evolution of fast and integrated neuronal signaling
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DOI：
10.1073/pnas.1416544112
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发表时间：
2015-01-27
影响因子：
11.1
通讯作者：
Bennett, Vann
中科院分区：
文献类型：
--
作者：
Jenkins, Paul M.;Kim, Namsoo;Bennett, Vann
轴突起始段（AIS）和朗氏结（Nodes of Ranvier）是有颌脊椎动物神经系统中电压门控钠通道（VGSC）的聚集部位，其促进快速长距离电信号。我们证明，近端轴突极性以及AIS的组装和Ranvier淋巴结的正常形态发生都需要迄今为止尚未表征的锚蛋白-G（AnkG）的选择性剪接巨型外显子。该外显子与I-连接蛋白/肌联蛋白具有序列相似性，并且在髓鞘发育之前，在早期脊椎动物中通过祖先ANK 2/ANK 3基因的第一轮全基因组复制后获得。巨大的外显子导致了一种新的神经系统特异性的480-kDa多肽，结合了先前已知的ANK重复序列和β-血影蛋白结合活性的特征，其纤维结构域长度接近150 nm。我们阐明了以前未描述的功能巨大的AnkG，包括招聘β 4血影蛋白的AIS，可能是由磷酸化调节，并证明480 kda的Ankg是一个主要组成部分的AIS膜“底涂层”成像铂复制电子显微镜。令人惊讶的是，巨大的AnkG敲除神经元完全缺乏已知的AIS组件仍然保留远端轴突极性，并产生动作电位（AP），虽然与异常的频率。巨大的AnkG缺陷小鼠可以活到断奶，并为患有严重认知功能障碍的人的生存提供了理论基础，这些人在巨大的外显子中携带截短突变。AnkG的巨大外显子是AIS和Ranvier节点组装所需的，并且是脊椎动物神经系统进化中的变革性创新，现在是神经发育障碍的潜在靶标。
Axon initial segments (AISs) and nodes of Ranvier are sites of clustering of voltage-gated sodium channels (VGSCs) in nervous systems of jawed vertebrates that facilitate fast long-distance electrical signaling. We demonstrate that proximal axonal polarity as well as assembly of the AIS and normal morphogenesis of nodes of Ranvier all require a heretofore uncharacterized alternatively spliced giant exon of ankyrin-G (AnkG). This exon has sequence similarity to I-connectin/Titin and was acquired after the first round of whole-genome duplication by the ancestral ANK2/ANK3 gene in early vertebrates before development of myelin. The giant exon resulted in a new nervous system-specific 480-kDa polypeptide combining previously known features of ANK repeats and beta-spectrin-binding activitywith a fibrous domain nearly 150 nm in length. We elucidate previously undescribed functions for giant AnkG, including recruitment of beta 4 spectrin to the AIS that likely is regulated by phosphorylation, and demonstrate that 480-kda Ankg is a major component of the AIS membrane "undercoat' imaged by platinum replica electron microscopy. Surprisingly, giant AnkG-knockout neurons completely lacking known AIS components still retain distal axonal polarity and generate action potentials (APs), although with abnormal frequency. Giant AnkG-deficient mice live to weaning and provide a rationale for survival of humans with severe cognitive dysfunction bearing a truncating mutation in the giant exon. The giant exon of AnkG is required for assembly of the AIS and nodes of Ranvier and was a transformative innovation in evolution of the vertebrate nervous system that now is a potential target in neurodevelopmental disorders.