Mechanisms of neural tube closure

神经管闭合是一个形态发生过程，涉及神经细胞的复杂行为。 极化神经板细胞有200多个基因参与了这一过程， 根据遗传模型，神经管异常是人类出生时最常见的 缺陷然而，神经管闭合的机制仍然知之甚少， 现有的脊椎动物模型是有限的。我们的初步实验已经确定了 在非洲爪蟾神经板的平面中几种蛋白质的独特极化， 证明了这种极性需要平面细胞极性（PCP） 和顶部-底部极性蛋白。拟议中的研究将进行现场成像的 神经板，使用一种新型的荧光传感器。新的分子， 与PCP复合物的关系将通过一种新的邻近和互补作用来确定， 基于生物素化的方法结合质谱。的参与 在神经管关闭期间PCP信号传导中的顶端-基底极性蛋白也将被 评估。爪蟾胚胎在任何发育阶段都很容易获得， 独特地适合于这些研究，允许快速分析蛋白质定位， 通过生物化学、胚胎学和细胞生物学的结合发挥作用 接近。这些实验将揭示基本的信号机制， 是中枢神经系统正常发育的基础拟议的研究是 与人类健康高度相关，因为这些信号通路的失调 导致大脑和神经管缺陷以及各种神经系统疾病。 .

Neural tube closure is a morphogenetic process that involves complex behaviors of polarized neural plate cells. With more than 200 genes implicated in this process in genetic models, neural tube abnormalities are among the most common human birth defects. Nevertheless, mechanisms of neural tube closure remain poorly understood and the available vertebrate models are limited. Our preliminary experiments have identified a unique polarization of several proteins in the plane of the Xenopus neural plate and demonstrated that this polarity requires the functions of both planar cell polarity (PCP) and apical-basal polarity proteins. The proposed studies will carry out live imaging of the neural plate using a novel fluorescent sensor. New molecules that physically associate with the PCP complex will be identified using a novel proximity- and complementation- based biotinylation approach combined with mass spectrometry. The involvement of the apical-basal polarity proteins in PCP signaling during neural tube closure will also be evaluated. Xenopus embryos are easily accessible at any developmental stage and are uniquely suited for these studies, allowing rapid analysis of protein localization and function through a combination of biochemical, embryological and cell biological approaches. These experiments will shed light on basic signaling mechanisms that underlie normal development of the central nervous system. The proposed studies are highly relevant to human health, because misregulation of these signaling pathways leads to brain and neural tube defects and a variety of neurological disorders.   .