Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development
Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development
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DOI：
10.1038/labinvest.3700376
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发表时间：
2006-02
影响因子：
5
通讯作者：
T. Seki;Kwon-Ho Hong;S. P. Oh
中科院分区：
文献类型：
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作者：
T. Seki;Kwon-Ho Hong;S. P. Oh
转化生长因子β（TGF-β）通过II型（TGFBR 2）和I型（激活素受体样激酶5，ALK 5; TGFBR 1）丝氨酸/苏氨酸激酶受体以及Smad 2/3的异源四聚体细胞表面复合物传递信号。我们之前已经证明，另一种I型受体ALK 1（ACVRL 1）也可以通过血管内皮细胞（EC）中BMP激活的Smads介导TGF-β信号。本课题组和其他研究者提出了一种假说，即血管内皮细胞中通过ALK 1和ALK 5的两条TGF-β信号通路可能在控制血管生成过程中内皮细胞的增殖和迁移方面发挥平衡作用。为了解决这种平衡在血管发育中的体内作用，我们创建了在Alk 5基因座（Alk 5 lacZ）中携带lacZ报告基因的敲入小鼠系。在整个发育过程中，在多个组织和器官中观察到Alk 5表达的明确定义的非普遍表达模式。总体而言，在软骨膜、骨膜和肾、肺和胆囊上皮细胞下面的间充质层中发现了高水平的Alk 5表达。在血管中，与动脉内皮中主要的Alk 1表达相比，Alk 5表达定位于血管的中膜和外膜层，但在内膜层中检测不到。此外，尽管Alk 5基因敲除的胚胎在血管平滑肌层的形成方面表现出缺陷，但血管的管腔是正确产生的，这与Alk 1基因敲除的小鼠中血管管腔的严重扩张形成了对比。Alk 1和Alk 5在血管中的这些相互排斥的表达模式，以及Alk 5无效胚胎中血管腔的不受干扰的形成，表明每个I型受体在血管发育中具有其独特的功能。Alk 5 lacZ小鼠将是在胚胎发育期间以及在不同病理条件下鉴定由Alk 5介导的TGF-β家族信号的体内细胞靶标的有价值的资源。
Transforming growth factor β (TGF-β) transmits signals through a heterotetrameric cell-surface complex of type II (TGFBR2) and type I (activin receptor-like kinase 5, ALK5; TGFBR1) serine/threonine kinase receptors, as well as Smad2/3. We have previously shown that another type I receptor, ALK1 (ACVRL1), can also mediate TGF-β signals via BMP-activated Smads in vascular endothelial cells (ECs). Our group and others have proposed the hypothesis that two TGF-β signaling pathways via ALK1 and ALK5 in vascular ECs may play a balancing role for controlling the proliferation and migration of ECs during angiogenesis. To address in vivo roles of this balance in vascular development, we have created a knockin mouse line that carries a lacZ reporter in the Alk5 gene locus (Alk5 lacZ). Throughout development, a well-defined, nonubiquitous expression pattern of Alk5 expression was observed in multiple tissues, and organs. Overall, a high level of Alk5 expression was found in perichondria, periostea, and the mesenchymal layers underlying epithelia in the kidney, lung, and gallbladder. In blood vessels, contrasting to predominant Alk1 expression in arterial endothelium, Alk5 expression was localized in the medial and adventitial layers of blood vessels, but was undetectable in the intimal layer. In addition, although Alk5-null embryos exhibit a defect in the formation of vascular smooth muscle layers, the lumens of blood vessels are generated properly, which stands in contrast to the severe dilation of the vascular lumens in Alk1-null mice. These mutually exclusive expression patterns of Alk1 and Alk5 in blood vessels, as well as the undisturbed formation of the vascular lumens in Alk5-null embryos, suggest that each type I receptor has its own unique functions in vascular development. The Alk5 lacZ mice will be a valuable resource in identifying the in vivo cellular targets of TGF-β family signals mediated by Alk5, both during embryonic development as well as in diverse pathological conditions.