Phillips Helen M, Murdoch Jennifer N, Chaudhry Bill, Copp Andrew J, Henderson Deborah J
Institute of Human Genetics, University of Newcastle upon Tyne, UK.
Circ Res. 2005 Feb 18;96(3):292-9. doi: 10.1161/01.RES.0000154912.08695.88. Epub 2005 Jan 6.
Loop-tail (Lp) mice develop double outlet right ventricle and aortic arch defects, and the defects are caused by mutations in the Vangl2 gene. Vangl2 mRNA is found in the outflow tract myocardium, including the myocardializing cells that migrate into the outflow tract cushions. Analysis of muscularization of the outflow tract septum showed that this process is compromised in Lp/Lp fetuses. Vangl2 is a component of the noncanonical Wnt, planar cell polarity (PCP) pathway that signals via RhoA. We therefore looked for evidence of polarization in myocardializing cells. In wild-type fetuses, myocardializing cells extend lamellipodia and filopodia into the cushion tissue and reorganize their actin cytoskeleton from a cortical form to stress fibers; behaviors that are characteristic of polarized cells. In contrast, Lp/Lp littermates do not extend lamellipodia or filopodia into the cushion tissue, and their actin remains in a cortical form, suggesting that polarized cell migration of myocardializing cells is inhibited in Lp/Lp. Several other components of the PCP pathway are also localized in the outflow tract myocardium. In wild-type fetuses, the myocardializing cells coexpress RhoA and one of its downstream mediators, ROCK1. RhoA expression is disrupted in Lp/Lp, and is lost from the myocardial-cushion tissue interface, including the presumptive myocardializing cells. These data suggest that Vangl2 is required for the polarization and movement of myocardializing cells into the outflow tract cushions, and that RhoA and ROCK1 are downstream mediators of the PCP signaling pathway in the developing outflow tract.
环形尾（Lp）小鼠会出现右心室双出口和主动脉弓缺陷，这些缺陷是由Vangl2基因突变引起的。在流出道心肌中发现了Vangl2 mRNA，包括迁移到流出道垫中的心肌化细胞。对流出道隔膜肌化的分析表明，这一过程在Lp/Lp胎儿中受到损害。Vangl2是非经典Wnt平面细胞极性（PCP）信号通路的一个组成部分，该通路通过RhoA进行信号传导。因此，我们寻找心肌化细胞极化的证据。在野生型胎儿中，心肌化细胞将片状伪足和丝状伪足延伸到垫组织中，并将其肌动蛋白细胞骨架从皮质形式重组为应力纤维；这些行为是极化细胞的特征。相比之下，Lp/Lp同窝小鼠的片状伪足和丝状伪足不会延伸到垫组织中，它们的肌动蛋白仍保持皮质形式，这表明Lp/Lp中，心肌化细胞的极化细胞迁移受到抑制。PCP信号通路的其他几个组成部分也定位于流出道心肌中。在野生型胎儿中，心肌化细胞共表达RhoA及其下游介质之一ROCK1。RhoA表达在Lp/Lp中被破坏，并且在心肌-垫组织界面（包括推定的心肌化细胞）中消失。这些数据表明，Vangl2是心肌化细胞向流出道垫极化和移动所必需的，并且RhoA和ROCK1是发育中的流出道中PCP信号通路的下游介质。
