Genetic ablation of polysialic acid causes severe neurodevelopmental defects rescued by deletion of the neural cell adhesion molecule
Genetic ablation of polysialic acid causes severe neurodevelopmental defects rescued by deletion of the neural cell adhesion molecule
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DOI：
10.1074/jbc.m511097200
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发表时间：
2005-12-30
影响因子：
4.8
通讯作者：
Hildebrandt, H
中科院分区：
文献类型：
--
作者：
Weinhold, B;Seidenfaden, R;Hildebrandt, H
聚α 2，8-唾液酸（polySia）是神经细胞粘附分子NCAM的独特修饰，与神经发育和可塑性密切相关。然而，归因于这种碳水化合物聚合物的重要作用受到了由于NCAM缺乏而缺乏polySia的小鼠的轻度表型的挑战。为了剖析polySia和NCAM功能，我们通过同时缺失两个聚唾液酸转移酶基因St 8 sia-II和St 8 sia-IV来产生polySia阴性但NCAM阳性的小鼠。除了与NCAM缺失动物共有的特征之外，还观察到具有特定脑布线缺陷、进行性脑积水、出生后生长迟缓和早熟死亡的严重表型。这些严重的缺陷通过额外删除NCAM而被选择性地挽救，这表明它们起源于由于polySia缺陷而获得的NCAM功能。本研究中提供的数据表明，polySia的重要作用在于小鼠大脑发育期间NCAM相互作用的控制和协调。此外，这第一次在体内证明，一个高度特异性的聚糖结构是更重要的比糖缀合物作为一个整体提供了一个新的观点蛋白质糖基化的复杂过程中建立脊椎动物大脑的相关性。
Poly-alpha 2,8-sialic acid (polySia) is a unique modification of the neural cell adhesion molecule, NCAM, tightly associated with neural development and plasticity. However, the vital role attributed to this carbohydrate polymer has been challenged by the mild phenotype of mice lacking polySia due to NCAM-deficiency. To dissect polySia and NCAM functions, we generated polySia-negative but NCAM-positive mice by simultaneous deletion of the two polysialyltransferase genes, St8sia-II and St8sia-IV. Beyond features shared with NCAM-null animals, a severe phenotype with specific brain wiring defects, progressive hydrocephalus, postnatal growth retardation, and precocious death was observed. These drastic defects were selectively rescued by additional deletion of NCAM, demonstrating that they originate from a gain of NCAM functions because of polySia deficiency. The data presented in this study reveal that the essential role of polySia resides in the control and coordination of NCAM interactions during mouse brain development. Moreover, this first demonstration in vivo that a highly specific glycan structure is more important than the glycoconjugate as a whole provides a novel view on the relevance of protein glycosylation for the complex process of building the vertebrate brain.