Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex
Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex
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DOI：
10.1038/ng1276
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发表时间：
2004-01-01
期刊：
影响因子：
30.8
通讯作者：
Walsh, CA
中科院分区：
文献类型：
--
作者：
Sheen, VL;Ganesh, VS;Walsh, CA
人类神经前体增殖的中断可导致小脑(小头畸形)，神经元迁移不当可导致侧脑室附近增殖区的大脑皮层神经元异常停滞(脑室周围异位)。在这里，我们发现了一种常染色体隐性遗传病，其特征是小头畸形和脑室周围异位症1，位于20号染色体上，由ADP核糖化因子鸟嘌呤核苷酸交换因子2(ARFGEF2)基因突变引起。通过Northern-Blot分析，我们发现小鼠Arfgef2的mRNA水平在胚胎期的神经元增殖和迁移中最高，通过原位杂交，我们发现该mRNA广泛分布于胚胎中枢神经系统(CNS)。ARFGEF2编码BFA抑制的大分子(>；200 kDa)布雷菲尔丁A(BFA)抑制的GEF2蛋白(BIG2)，它是跨高尔基体网络(TGN)运输囊泡和膜所必需的。在体外，BFA或显性负ARFGEF2基因抑制BIG2会减少细胞增殖，这表明神经扩张是细胞自主调节的。抑制BIG2也干扰了E-钙粘蛋白和β-连环素等分子在细胞内的定位，阻止了它们从高尔基体到细胞表面的运输。我们的发现表明，囊泡运输是人脑皮质发育过程中增殖和迁移的重要调节因素。
Disruption of human neural precursor proliferation can give rise to a small brain ( microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia 1 maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northern-blot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS). ARFGEF2 encodes the large (>200 kDa) brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is required for vesicle and membrane trafficking from the trans-Golgi network (TGN). Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin and beta-catenin by preventing their transport from the Golgi apparatus to the cell surface. Our findings show that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development.