L1 cell adhesion molecule signal cascades: Targets for ethanol developmental neurotoxicity
L1 cell adhesion molecule signal cascades: Targets for ethanol developmental neurotoxicity
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DOI：
10.1016/s0161-813x(01)00034-1
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发表时间：
2001-10-01
期刊：
影响因子：
3.4
通讯作者：
Bearer, CF
中科院分区：
文献类型：
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作者：
Bearer, CF
指导神经发育的主要机制是通过细胞-细胞和细胞-基质粘附以及由细胞粘附分子（CAM）介导的信号传导。大多数CAM被分为三个家族：钙粘蛋白，整合素和免疫球蛋白超家族的成员，包括L1。虽然新的受体和基质成分的阐明已经成为一个频繁发生的事件，阐明它们的运作机制，这些机制在复杂的发育事件的功能仍然是基本的。所有三个家族的成员参与差异粘附、信号转导和物理/机械效应。这些作用模式中的每一种都是发育神经毒物的潜在靶点。在这篇简短的综述中，将总结L1在正常和异常神经发育中的作用。L1是细胞表面跨膜糖蛋白，在X染色体上具有单拷贝基因。有两个选择性剪接的外显子，其中RSLE包含仅在有丝分裂后神经元的轴突和生长锥上发现的形式。L1介导以下功能：粘附、神经突延伸、神经元迁移和轴突成束。L1对正常神经发育至关重要; L1基因缺陷的人，称为胼胝体发育不全、智力迟钝、拇指内收、痉挛和脑积水（CRASH）综合征，以及L1表达缺乏的小鼠，具有广泛的神经病理学和异常行为。胎儿酒精综合征患者与CRASH患者具有相似特征的观察结果导致了对乙醇对L1影响的研究。生理浓度的乙醇已被证明可以抑制小脑颗粒神经元中L1介导的神经突生长。这种抑制可能是由于表达降低、细胞表面分布改变、信号转导受损或与细胞骨架的相互作用受损。这些数据表明，L1及其相关的信号通路是发育神经毒物的潜在目标。(C)2001 Elsevier Science Inc. All rights reserved.
A major mechanism guiding neural development is through cell-cell and cell-matrix adhesions and signaling mediated by, cell adhesion molecules (CAMs). The majority of CAMs have been grouped into three families: the cadherins, the integrins and the members of the immunoglobulin superfamily including L1. While the elucidation of new receptors and matrix components has become a frequent occurrence, the elucidation of the mechanisms by which they operate, and the function of those mechanisms in complex developmental events remains rudimentary. Members of all three families participate in differential adhesion, signal transduction and physical/mechanical effects. Each of these modes of action is a potential target for developmental neurotoxicants. In this brief review, the role of L1 in normal and abnormal neurodevelopment will be summarized. L1 is a cell surface transmembrane glycoprotein with a single copy gene on the X chromosome. There are two alternatively spliced exons, with the RSLE containing form found only on axons and growth cones of post-mitotic neurons. L1 mediates the following functions: adhesion, neurite extension, neuronal migration, and axon fasciculation. L1 is critical for normal neural development; humans with genetic defects in L1, termed corpus callosum hypoplasia, mental retardation, adducted thumbs, spasticity and hydrocephalus (CRASH) syndrome, and mice lacking expression of L1 have extensive neuropathologic and aberrant behaviors. The observation that patients with fetal alcohol syndrome share similar features to patients with CRASH has lead to the investigation of the effects of ethanol on L1. Physiologic concentrations of ethanol have been shown to inhibit L1 mediated neurite outgrowth in cerebellar granule neurons. Such inhibition may result from decreased expression, altered cell surface distribution, impaired signal transduction, or impaired interaction with the cytoskeleton. These data indicate that L1 and its associated signaling pathways are potentially targets for developmental neurotoxicants. (C) 2001 Elsevier Science Inc. All rights reserved.