Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice
Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice
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DOI：
10.1172/jci27597
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发表时间：
2006-07-01
影响因子：
15.9
通讯作者：
Shen, Sanbing
中科院分区：
文献类型：
--
作者：
Lang, Bing;Song, Bing;Shen, Sanbing
脑积水是一种影响中枢神经系统的常见且具有潜在破坏性的出生缺陷，其与 G 蛋白偶联受体 (GPCR) 的关系尚不清楚。我们已经在小鼠神经系统中表达了 2、4 或 6 个拷贝的 GPCR（具有 130 kb 转基因的人类 PAC1 受体），其模式与静脉内基因的模式非常相似。与 PAC1 的作用一致，Tg 小鼠大脑中的 PKA 和 PKC 活性升高。值得注意的是，Tg 小鼠出现了剂量依赖性脑积水样特征，包括第三脑室和侧脑室扩大以及大脑皮层、胼胝体和连合下器官（SCO）减少。神经元增殖和凋亡与脑积水有关，我们观察到 Tg 胚胎发育中的皮层和 SCO 中神经元增殖显着减少，神经元凋亡大量增加，而体外神经突生长和神经元迁移仍然不受影响。心室室管膜纤毛对于引导脑脊液流动至关重要，Tg 小鼠的室管膜表现出纤毛破坏，磷酸化 CREB 免疫反应性增加。这些数据表明，改变的神经元增殖/凋亡和破坏的室管膜纤毛是导致PAC1过表达小鼠脑积水的主要因素。据我们所知，这是第一份报告证明 GPCR 的失调可能与脑积水相关的神经发育障碍有关。
Hydrocephalus is a common and potentially devastating birth defect affecting the CNS, and its relationship with G protein-coupled receptors (GPCRs) is unknown. We have expressed 2, 4, or 6 copies of a GPCR - the human PAC1 receptor with a 130-kb transgene in the mouse nervous system in a pattern closely resembling that of the endovenous gene. Consistent with PAC1 actions, PKA and PKC activity were elevated in the brains of Tg mice. Remarkably, Tg mice developed dose-dependent hydrocephalus-like characteristics, including enlarged third and lateral ventricles and reduced cerebral cortex, corpus callosum, and subcommissural organ (SCO). Neuronal proliferation and apoptosis were implicated in hydrocephalus, and we observed significantly reduced neuronal proliferation and massively increased neuronal apoptosis in the developing cortex and SCO of Tg embryos, while neurite outgrowth and neuronal migration in vitro remain uncompromised. Ventricular ependymal cilia are crucial for directing cerebrospinal fluid flow, and ependyma of Tg mice exhibited disrupted cilia with increased phospho-CREB immunoreactivity. These data demonstrate that altered neuronal proliferation/apoptosis and disrupted ependymal cilia are the main factors contributing to hydrocephalus in PACl-overexpressing mice. This is the first report to our knowledge demonstrating that misregulation of GPCRs can be involved in hydrocephalus-related neurodevelopmental disorders.