Neurulation and neurite extension require the zinc transporter ZIP12 (slc39a12)
Neurulation and neurite extension require the zinc transporter ZIP12 (slc39a12)
复制标题
DOI：
10.1073/pnas.1222142110
复制
发表时间：
2013-06-11
影响因子：
11.1
通讯作者：
Messerli, Mark A.
中科院分区：
文献类型：
--
作者：
Chowanadisai, Winyoo;Graham, David M.;Messerli, Mark A.
神经元结构和功能的许多方面都需要 Zn2+。然而，人们对 Zn2+ 在神经系统中的调节仍知之甚少。对组织分析微阵列数据的系统分析表明，锌转运蛋白 ZIP12 (slc39a12) 在人脑中高度表达。在此报告的工作中，我们证实 ZIP12 是一种 Zn2+ 摄取转运蛋白，在小鼠和非洲爪蟾神经系统中具有保守的高表达模式。 ZIP12 敲除后，小鼠神经元和 Neuro-2a 细胞产生更少和更短的神经突，而不影响细胞活力。 Zn2+ 螯合或负载到细胞中以改变 Zn2+ 的可用性，分别模拟或减少 ZIP12 敲低对神经突生长的影响。 ZIP12 敲除减少了 cAMP 反应元件结合蛋白丝氨酸 133 的激活和磷酸化，这是神经元分化的关键途径。组成型 cAMP 反应元件结合蛋白激活可恢复由 Zn2+ 螯合或 ZIP12 敲低引起的神经突生长损伤。 ZIP12 敲低还会减少微管蛋白聚合，并增加神经突生长后对诺考达唑的敏感性。我们发现 ZIP12 在热带爪蟾的神经形成和早期神经系统发育过程中表达，其中 ZIP12 反义吗啉敲低会损害神经管闭合并阻止神经形成过程中的发育，同时减少神经板中微管蛋白聚合。这项研究确定了神经系统发育特别需要的 Zn2+ 转运蛋白，并提供了 Zn2+、神经形成和神经元分化之间的切实联系。
Zn2+ is required for many aspects of neuronal structure and function. However, the regulation of Zn2+ in the nervous system remains poorly understood. Systematic analysis of tissue-profiling microarray data showed that the zinc transporter ZIP12 (slc39a12) is highly expressed in the human brain. In the work reported here, we confirmed that ZIP12 is a Zn2+ uptake transporter with a conserved pattern of high expression in the mouse and Xenopus nervous system. Mouse neurons and Neuro-2a cells produce fewer and shorter neurites after ZIP12 knockdown without affecting cell viability. Zn2+ chelation or loading in cells to alter Zn2+ availability respectively mimicked or reduced the effects of ZIP12 knockdown on neurite outgrowth. ZIP12 knockdown reduces cAMP response element-binding protein activation and phosphorylation at serine 133, which is a critical pathway for neuronal differentiation. Constitutive cAMP response element-binding protein activation restores impairments in neurite outgrowth caused by Zn2+ chelation or ZIP12 knockdown. ZIP12 knockdown also reduces tubulin polymerization and increases sensitivity to nocodazole following neurite outgrowth. We find that ZIP12 is expressed during neurulation and early nervous system development in Xenopus tropicalis, where ZIP12 antisense morpholino knockdown impairs neural tube closure and arrests development during neurulation with concomitant reduction in tubulin polymerization in the neural plate. This study identifies a Zn2+ transporter that is specifically required for nervous system development and provides tangible links between Zn2+, neurulation, and neuronal differentiation.