像脊柱裂这样的脊髓疾病，在病情发展过程中，脊髓细胞生长平坦，不能卷起形成椎管。根据12月6日Nature Cell Biology上的一篇文章，约翰霍普金斯大学医学院和加州大学伯克利分校的科学家发现了一个先前未知的关于蛋白运输和老鼠脊髓发展的关联。这项发现为脊髓缺陷研究开辟了新的道路。
神经学教授David Ginty介绍说，这项研究最让人欣喜的地方是，发现了脊髓缺陷与蛋白质分泌体系和神经管封闭的关联。
研究团队开始是以发现新基因作为研究出发点的，这些新的基因参与引导神经系统中数千亿神经元通路的形成。他们随机设计了老鼠基因的变异，然后繁殖老鼠后代并检测后代神经系统发展的缺陷，在数千的培育老鼠中发现，有一个老鼠的胚胎，其脊髓不能形成封闭管。
研究人员识别了该老鼠中变异的基因，该基因叫Sec24b，其在细胞包装新生成的蛋白质方面承担了重要的作用。而这些蛋白最终将要被传送到细胞膜上或者细胞外。
此外，还存在另一个基因Vangl2，其变异能导致非常显著的脊髓封闭缺陷，因此研究人员试着检测是否Vangl2和Sec24b会互作。他们设计了同时含有这两种基因的老鼠，发现68%的老鼠有脊髓封闭缺陷情况出现，超过一半的老鼠在出生后4周内死亡，表明这两种基因是相互作用的。
由于上述的两种蛋白涉及神经管封闭，研究小组认为可能Sec24b变异影响了Vangl2的包装。在混合了细胞成分和Vangl2的试管中，研究人员分别加入了Sec24b或其他相关的蛋白，结果只包含Sec24b的试管能够包装Vangl2，其他相关的蛋白则不能。
推荐原始出处：
Nature Cell Biology 12, 41 - 46 (2010) 6 December 2009 | doi:10.1038/ncb2002
Sec24b selectively sorts Vangl2 to regulate planar cell polarity during neural tube closure
Janna Merte1,4, Devon Jensen2,4, Kevin Wright1, Sarah Sarsfield1, Yanshu Wang3, Randy Schekman2 " David D. Ginty1
Craniorachischisis is a rare but severe birth defect that results in a completely open neural tube. Mouse mutants in planar cell polarity (PCP) signalling components have deficits in the morphological movements of convergent extension that result in craniorachischisis. Using a forward genetic screen in mice, we identified Sec24b, a cargo-sorting member of the core complex of the endoplasmic reticulum (ER)-to-Golgi transport vesicle COPII, as critical for neural tube closure. Sec24bY613 mutant mice exhibit craniorachischisis, deficiencies in convergent extension and other PCP-related phenotypes. Vangl2, a key component of the PCP-signalling pathway critical for convergent extension, is selectively sorted into COPII vesicles by Sec24b. Moreover, Sec24bY613 genetically interacts with a loss-of-function Vangl2 allele (Vangl2LP), causing a marked increase in the prevalence of spina bifida. Interestingly, the Vangl2 looptail point mutants Vangl2D255E and Vangl2S464N, known to cause defects in convergent extension, fail to sort into COPII vesicles and are trapped in the ER. Thus, during COPII vesicle formation, Sec24b shows cargo specificity for a core PCP component, Vangl2, of which proper ER-to-Golgi transport is essential for the establishment of PCP, convergent extension and closure of the neural tube.
1 The Solomon H. Snyder Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, MD 21205, USA.
2 Department of Molecular and Cell Biology and Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA 94720, USA.
3 Department of Molecular Biology and Genetics and Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, MD 21205, USA.
4 These authors contributed equally to this work.
