Developmental regulation of neural cell adhesion molecule in human prefrontal cortex.
Developmental regulation of neural cell adhesion molecule in human prefrontal cortex.
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DOI：
10.1016/j.neuroscience.2009.04.037
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发表时间：
2009-08-04
期刊：
影响因子：
3.3
通讯作者：
Jarskog, L. F.
中科院分区：
文献类型：
--
作者：
Cox, E. T.;Brennaman, L. H.;Gable, K. L.;Hamer, R. M.;Glantz, L. A.;Lamantia, A. -S.;Lieberman, J. A.;Gilmore, J. H.;Maness, P. F.;Jarskog, L. F.
神经细胞粘附分子（NCAM）是一种膜结合的细胞识别分子，在正常神经发育中发挥重要作用，包括细胞迁移，神经突生长，轴突成束和突触可塑性。NCAM mRNA的选择性剪接产生三种主要的蛋白质同种型：NCAM-180、-140和-120。NCAM同种型的胞外结构域脱落可产生胞外105-115 kDa可溶性NCAM片段（NCAM-EC）和较小的胞内胞质片段（NCAM-IC）。NCAM还通过添加聚唾液酸（PSA）-NCAM在脑中经历独特的翻译后修饰。有趣的是，PSA-NCAM和NCAM-EC都与精神分裂症的病理生理学有关。主要NCAM亚型和PSA-NCAM的发育表达模式已在啮齿动物脑中描述，但没有研究检查NCAM在人类皮质发育中的表达。采用Western印迹法对42名年龄从妊娠中期到成年早期的人死后前额叶皮层中的NCAM进行定量。每种NCAM亚型（NCAM-180、-140和-120）、翻译后修饰（PSA-NCAM）和切割片段（NCAM-EC和NCAM-IC）均在额叶皮层中表现出发育调节。NCAM-180、-140和-120，以及PSA-NCAM和NCAM-IC在胎儿和出生后早期都显示出强的发育调节，与它们在轴突生长和可塑性中的鉴定作用一致。NCAM-EC表现出从出生后早期逐渐增加到青春期早期达到平台，可能涉及后期发育过程。总之，这项研究表明，主要的NCAM亚型，PSA- NCAM和蛋白水解切割的NCAM在人前额叶皮层的出生前和出生后的发展。这些数据为人类皮质发育提供了新的见解，也为特定发育间隔期间改变的NCAM信号传导如何影响突触连接和回路形成提供了基础，从而有助于神经发育障碍。
Neural cell adhesion molecule (NCAM) is a membrane-bound cell recognition molecule that exerts important functions in normal neurodevelopment including cell migration, neurite outgrowth, axon fasciculation, and synaptic plasticity. Alternative splicing of NCAM mRNA generates three main protein isoforms: NCAM-180, -140, and -120. Ectodomain shedding of NCAM isoforms can produce an extracellular 105–115 kDa soluble NCAM fragment (NCAM-EC) and a smaller intracellular cytoplasmic fragment (NCAM-IC). NCAM also undergoes a unique post-translational modification in brain by the addition of polysialic acid (PSA)-NCAM. Interestingly, both PSA-NCAM and NCAM-EC have been implicated in the pathophysiology of schizophrenia. The developmental expression patterns of the main NCAM isoforms and PSA-NCAM have been described in rodent brain, but no studies have examined NCAM expression across human cortical development. Western blotting was used to quantify NCAM in human postmortem prefrontal cortex in 42 individuals ranging in age from mid-gestation to early adulthood. Each NCAM isoform (NCAM-180, -140, and -120), post-translational modification (PSA-NCAM) and cleavage fragment (NCAM-EC and NCAM-IC) demonstrated developmental regulation in frontal cortex. NCAM-180, -140, and -120, as well as PSA-NCAM, and NCAM-IC all showed strong developmental regulation during fetal and early postnatal ages, consistent with their identified roles in axon growth and plasticity. NCAM-EC demonstrated a more gradual increase from the early postnatal period to reach a plateau by early adolescence, potentially implicating involvement in later developmental processes. In summary, this study implicates the major NCAM isoforms, PSA- NCAM and proteolytically cleaved NCAM in pre- and postnatal development of the human prefrontal cortex. These data provide new insights on human cortical development and also provide a basis for how altered NCAM signaling during specific developmental intervals could affect synaptic connectivity and circuit formation, and thereby contribute to neurodevelopmental disorders.
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