Tra2beta as a novel mediator of vascular smooth muscle diversification.
Tra2beta as a novel mediator of vascular smooth muscle diversification.
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Tra2beta 作为血管平滑肌多样化的新型介质。
DOI：
10.1161/circresaha.108.178384
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发表时间：
2008
影响因子：
20.1
通讯作者：
Fisher,StevenA
中科院分区：
文献类型：
--
作者：
Shukla,Supriya;Fisher,StevenA
变压器剪接调节蛋白决定果蝇的性二态性特征。 Tra-2 的脊椎动物同源物在表型规范中的作用尚不清楚。我们使用 MYPT1 E23 外显子的选择性剪接作为模型来研究平滑肌多样化为快速和慢速收缩表型。与大动脉和静脉的慢平滑肌组织（其中 E23 被跳过）相比，Tra2β mRNA 和蛋白质在快速平滑肌组织（如大鼠门静脉和小肠系膜动脉）（其中 E23 被剪接）中的表达水平高出 10 倍。随着大鼠门静脉和禽砂囊在围产期执行基因表达的快速程序，Tra2β 与 E23 剪接的启动一致上调高达 10 倍。在门静脉高压和肠系膜动脉高/低流量等疾病模型中，门静脉和肠系膜一级动脉动态下调 Tra2β，与 E23 跳跃的转变和基因表达的缓慢程序一致。 Tra2β 与 E23 内高度保守的序列结合，并在体外和体内反式激活其剪接；通过突变或删除该序列即可消除这一点。 RNA 干扰介导的 Tra2β 敲低显着减少了 E23 剪接。我们认为，Tra2β 在进化过程中得到了保守，并被重新部署用于快速平滑肌表型的规范，并且可以作为发育和疾病模型中这一过程研究的新节点。
Transformer splicing regulatory proteins determine the sexually dimorphic traits ofDrosophila. The role of the vertebrate homologs of Tra-2 in phenotypic specification is undefined. We are using the alternative splicing of the MYPT1 E23 exon as a model for the study of smooth muscle diversification into fast and slow contractile phenotypes. Tra2β mRNA and protein is expressed at up to 10-fold higher levels in fast smooth muscle tissues such as the rat portal vein and small mesenteric artery, in which E23 is spliced, as compared to the slow smooth muscle tissues of the large arteries and veins, in which E23 is skipped. Tra2β is upregulated up to 10-fold concordant with the initiation of E23 splicing as the rat portal vein and avian gizzard implement the fast program of gene expression in the perinatal period. In disease models such as portal hypertension and mesenteric artery high/low flow, the portal vein and first order mesenteric artery dynamically downregulate Tra2β concordant with a shift to E23 skipping and the slow program of gene expression. Tra2β binds to a highly conserved sequence within E23 and transactivates its splicing in vitro and in vivo; this is abolished with mutation or deletion of this sequence. RNA interference–mediated knockdown of Tra2β markedly reduces E23 splicing. We propose that Tra2β has been conserved through evolution and redeployed for the specification of the fast smooth muscle phenotype and may serve as a novel nodal point for the investigation of this process in developmental and disease models.