Ferland Russell J, Batiz Luis Federico, Neal Jason, Lian Gewei, Bundock Elizabeth, Lu Jie, Hsiao Yi-Chun, Diamond Rachel, Mei Davide, Banham Alison H, Brown Philip J, Vanderburg Charles R, Joseph Jeffrey, Hecht Jonathan L, Folkerth Rebecca, Guerrini Renzo, Walsh Christopher A, Rodriguez Esteban M, Sheen Volney L
Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Hum Mol Genet. 2009 Feb 1;18(3):497-516. doi: 10.1093/hmg/ddn377. Epub 2008 Nov 7.
Periventricular heterotopia (PH) is a disorder characterized by neuronal nodules, ectopically positioned along the lateral ventricles of the cerebral cortex. Mutations in either of two human genes, Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2), cause PH (Fox et al. in 'Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia'. Neuron, 21, 1315-1325, 1998; Sheen et al. in 'Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex'. Nat. Genet., 36, 69-76, 2004). Recent studies have shown that mutations in mitogen-activated protein kinase kinase kinase-4 (Mekk4), an indirect interactor with FlnA, also lead to periventricular nodule formation in mice (Sarkisian et al. in 'MEKK4 signaling regulates filamin expression and neuronal migration'. Neuron, 52, 789-801, 2006). Here we show that neurons in post-mortem human PH brains migrated appropriately into the cortex, that periventricular nodules were primarily composed of later-born neurons, and that the neuroependyma was disrupted in all PH cases. As studied in the mouse, loss of FlnA or Big2 function in neural precursors impaired neuronal migration from the germinal zone, disrupted cell adhesion and compromised neuroepithelial integrity. Finally, the hydrocephalus with hop gait (hyh) mouse, which harbors a mutation in Napa [encoding N-ethylmaleimide-sensitive factor attachment protein alpha (alpha-SNAP)], also develops a progressive denudation of the neuroepithelium, leading to periventricular nodule formation. Previous studies have shown that Arfgef2 and Napa direct vesicle trafficking and fusion, whereas FlnA associates dynamically with the Golgi membranes during budding and trafficking of transport vesicles. Our current findings suggest that PH formation arises from a final common pathway involving disruption of vesicle trafficking, leading to impaired cell adhesion and loss of neuroependymal integrity.
室周异位（PH）是一种以神经元结节为特征的疾病，这些结节异位位于大脑皮质侧脑室周围。人类基因细丝蛋白A（FLNA）或ADP核糖基化因子鸟嘌呤交换因子2（ARFGEF2）中的任何一个发生突变都会导致PH（福克斯等人，“细丝蛋白1突变阻止人类室周异位中大脑皮质神经元的迁移”。《神经元》，21卷，1315 - 1325页，1998年；申等人，“ARFGEF2突变表明囊泡运输与人类大脑皮质神经祖细胞增殖和迁移有关”。《自然遗传学》，36卷，69 - 76页，2004年）。最近的研究表明，有丝分裂原激活蛋白激酶激酶激酶4（Mekk4）发生突变，Mekk4是与FlnA的间接相互作用因子，也会导致小鼠室周结节形成（萨尔基西安等人，“MEKK4信号调节细丝蛋白表达和神经元迁移”。《神经元》，52卷，789 - 801页，2006年）。在这里我们表明，死后人类PH脑内的神经元能正常迁移到皮质，室周结节主要由较晚生成（出生）的神经元组成，并且在所有PH病例中神经室管膜均被破坏。正如在小鼠中所研究的，神经前体细胞中FlnA或Big2功能的丧失会损害神经元从生发区的迁移，破坏细胞黏附并损害神经上皮的完整性。最后，脑积水伴跳跃步态（hyh）小鼠，其Napa基因（编码N -乙基马来酰亚胺敏感因子附着蛋白α（α - SNAP））发生突变，也会出现神经上皮的进行性剥脱，导致室周结节形成。先前的研究表明，Arfgef2和Napa指导囊泡运输和融合，而FlnA在运输囊泡出芽和运输过程中与高尔基体膜动态结合。我们目前的研究结果表明，PH的形成源于涉及囊泡运输破坏的最终共同途径，导致细胞黏附受损和神经室管膜完整性丧失。
