Emergence of Xin demarcates a key innovation in heart evolution.
Emergence of Xin demarcates a key innovation in heart evolution.
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DOI：
10.1371/journal.pone.0002857
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发表时间：
2008-08-06
期刊：
影响因子：
3.7
通讯作者：
Lin, Jim Jung-Ching
中科院分区：
文献类型：
--
作者：
Grosskurth, Shaun E.;Bhattacharya, Debashish;Wang, Qinchuan;Lin, Jim Jung-Ching
小鼠含 Xin 重复序列的蛋白（mXinα 和 mXinβ）定位于心脏的闰盘。 mXinα 能够捆绑肌动蛋白丝并与 β-连环蛋白相互作用，表明其在将肌动蛋白细胞骨架与 N-钙粘蛋白/β-连环蛋白粘附连接起来方面发挥着作用。 mXinα缺失小鼠心脏的闰盘超微结构逐渐发生改变，并出现心脏肥大和伴有传导缺陷的心肌病。 mXinα 缺陷小鼠中 mXinβ 的上调表明对 mXinα 损失的部分补偿。为了阐明这些蛋白质之间的进化关系并确定 Xin 的起源，对 40 种脊椎动物 Xins 进行了系统发育分析。我们的研究结果表明，祖先Xin起源于七鳃鳗出现之前，随后在脊椎动物谱系的早期经历了基因复制。随后的硬骨鱼特异性基因组复制导致大多数硬骨鱼编码至少三个基因。所有 Xins 在 Xin 重复区域内都含有高度保守的 β-连环蛋白结合结构域。与小鼠 Xins 类似，鸡、青蛙和斑马鱼 Xins 也与 β-连环蛋白共定位于看似闰盘的结构。所有 Xins N 末端的假定 DNA 结合域都是高度保守的，而之前表征的 Mena/VASP 结合域是仅在来自胎盘哺乳动物的 Xinαs 中发现的衍生性状。在 C 末端，Xinα 和 Xinβ 彼此之间差异更大，但来自哺乳动物的每种同种型均显示出高度的同种型内序列同一性。这表明哺乳动物 Xinα 和 Xinβ 具有不同但保守的功能。有趣的是，辛的起源。 5.5亿年前，恰逢具有完整内皮层和心肌层的心室的形成。我们假设Xin旁系同源物的出现及其功能分化可能在心脏的进化发展中发挥了关键作用。
The mouse Xin repeat-containing proteins (mXinα and mXinβ) localize to the intercalated disc in the heart. mXinα is able to bundle actin filaments and to interact with β-catenin, suggesting a role in linking the actin cytoskeleton to N-cadherin/β-catenin adhesion. mXinα-null mouse hearts display progressively ultrastructural alterations at the intercalated discs, and develop cardiac hypertrophy and cardiomyopathy with conduction defects. The up-regulation of mXinβ in mXinα-deficient mice suggests a partial compensation for the loss of mXinα. To elucidate the evolutionary relationship between these proteins and to identify the origin of Xin, a phylogenetic analysis was done with 40 vertebrate Xins. Our results show that the ancestral Xin originated prior to the emergence of lamprey and subsequently underwent gene duplication early in the vertebrate lineage. A subsequent teleost-specific genome duplication resulted in most teleosts encoding at least three genes. All Xins contain a highly conserved β-catenin-binding domain within the Xin repeat region. Similar to mouse Xins, chicken, frog and zebrafish Xins also co-localized with β-catenin to structures that appear to be the intercalated disc. A putative DNA-binding domain in the N-terminus of all Xins is strongly conserved, whereas the previously characterized Mena/VASP-binding domain is a derived trait found only in Xinαs from placental mammals. In the C-terminus, Xinαs and Xinβs are more divergent relative to each other but each isoform from mammals shows a high degree of within-isoform sequence identity. This suggests different but conserved functions for mammalian Xinα and Xinβ. Interestingly, the origin of Xin ca. 550 million years ago coincides with the genesis of heart chambers with complete endothelial and myocardial layers. We postulate that the emergence of the Xin paralogs and their functional differentiation may have played a key role in the evolutionary development of the heart.
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