An evolutionary recent neuroepithelial cell adhesion function of huntingtin implicates ADAM10-Ncadherin
An evolutionary recent neuroepithelial cell adhesion function of huntingtin implicates ADAM10-Ncadherin
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DOI：
10.1038/nn.3080
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发表时间：
2012-05-01
影响因子：
25
通讯作者：
Cattaneo, Elena
中科院分区：
文献类型：
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作者：
Lo Sardo, Valentina;Zuccato, Chiara;Cattaneo, Elena
亨廷顿氏病的基因产物亨廷顿蛋白对于神经管的形成是不可或缺的，但其作用尚不清楚。我们研究了 htt-null 胚胎干细胞和 htt-morpholino 斑马鱼胚胎的神经形成，发现了这种古老蛋白质的一个以前未知的、进化上最近的功能。我们发现 htt 对于神经上皮细胞之间的同型相互作用至关重要；它通过调节金属蛋白酶 ADAM 10 活性和 Ncadherin 裂解来允许神经形成和玫瑰花结形成。该功能嵌入 htt 的 N 末端，并通过使用 ADAM 10 抑制剂处理 htt 敲低斑马鱼来进行表型复制。值得注意的是，在 htt 缺失细胞中，无玫瑰花环表型的逆转仅在来自后口动物生物体的进化上最近的 htt 异源物表达时发生。相反，我们测试的所有异源物，包括来自果蝇和盘基网柄菌的 htt，都表现出抗凋亡活性。因此，抗细胞凋亡可能是 htt 的祖先功能之一，但在后口动物中，htt 进化出一种独特的调节活性，通过 ADAM10-Ncadherin 控制神经粘附，这对大脑的进化和发育具有影响。
The Huntington's disease gene product, huntingtin, is indispensable for neural tube formation, but its role is obscure. We studied neurulation in htt-null embryonic stem cells and htt-morpholino zebrafish embryos and found a previously unknown, evolutionarily recent function for this ancient protein. We found that htt was essential for homotypic interactions between neuroepithelial cells; it permitted neurulation and rosette formation by regulating metalloprotease ADAM 10 activity and Ncadherin cleavage. This function was embedded in the N terminus of htt and was phenocopied by treatment of htt knockdown zebrafish with an ADAM 10 inhibitor. Notably, in htt-null cells, reversion of the rosetteless phenotype occurred only with expression of evolutionarily recent htt heterologues from deuterostome organisms. Conversely, all of the heterologues that we tested, including htt from Drosophila melanogaster and Dictyostelium discoideum, exhibited anti-apoptotic activity. Thus, anti-apoptosis may have been one of htt's ancestral function(s), but, in deuterostomes, htt evolved to acquire a unique regulatory activity for controlling neural adhesion via ADAM10-Ncadherin, with implications for brain evolution and development.