Neogenin and RGMa Control Neural Tube Closure and Neuroepithelial Morphology by Regulating Cell Polarity
Neogenin and RGMa Control Neural Tube Closure and Neuroepithelial Morphology by Regulating Cell Polarity
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DOI：
10.1523/jneurosci.4265-08.2008
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发表时间：
2008-11-26
影响因子：
5.3
通讯作者：
Cooper, Helen M.
中科院分区：
文献类型：
--
作者：
Kee, Nigel;Wilson, Nicole;Cooper, Helen M.
在人类中，神经管闭合缺陷的发生率为1：1000。设计新的策略来预防这种常见的缺陷将受益于对神经胚形成的分子事件的进一步理解。神经褶提升是神经形成过程中驱动神经管闭合的关键形态学过程。然而，到目前为止，支持神经褶皱升高的分子途径尚未阐明。在这里，我们使用吗啉敲低技术来证明，排斥性指导分子（RGMa）-再生蛋白的相互作用是至关重要的有效的神经折叠海拔非洲爪蟾神经形成过程中，这些分子的损失导致破坏神经管关闭。我们证明，再生蛋白和RGMa是建立整个神经形成的神经板中的深层细胞的形态所必需的。我们还表明，再生蛋白的损失严重破坏了深层细胞内的微管网络，这表明深层细胞内的再生蛋白依赖性微管组织对于与上覆的表面细胞层的径向嵌入是必不可少的，从而驱动神经褶皱的提升。此外，我们表明，持续再生蛋白活性也是必要的建立apicobasally极化假复层神经上皮的神经管。因此，我们的研究确定了一种新的信号通路，在神经褶皱的提升和神经管形态发生的放射状嵌入和上皮化必不可少。
In humans, neural tube closure defects occur in 1: 1000 pregnancies. The design of new strategies for the prevention of such common defects would benefit from an improved understanding of the molecular events underlying neurulation. Neural fold elevation is a key morphological process that acts during neurulation to drive neural tube closure. However, to date, the molecular pathways underpinning neural fold elevation have not been elucidated. Here, we use morpholino knock-down technology to demonstrate that Repulsive Guidance Molecule (RGMa)-Neogenin interactions are essential for effective neural fold elevation during Xenopus neurulation and that loss of these molecules results in disrupted neural tube closure. We demonstrate that Neogenin and RGMa are required for establishing the morphology of deep layer cells in the neural plate throughout neurulation. We also show that loss of Neogenin severely disrupts the microtubule network within the deep layer cells suggesting that Neogenin-dependent microtubule organization within the deep cells is essential for radial intercalation with the overlying superficial cell layer, thereby driving neural fold elevation. In addition, we show that sustained Neogenin activity is also necessary for the establishment of the apicobasally polarized pseudostratified neuroepithelium of the neural tube. Therefore, our study identifies a novel signaling pathway essential for radial intercalation and epithelialization during neural fold elevation and neural tube morphogenesis.