SEC14 and Spectrin Domains 1 (Sestd1), Dishevelled 2 (Dvl2) and Dapper Antagonist of Catenin-1 (Dact1) co-regulate the Wnt/Planar Cell Polarity (PCP) pathway during mammalian development.
SEC14 and Spectrin Domains 1 (Sestd1), Dishevelled 2 (Dvl2) and Dapper Antagonist of Catenin-1 (Dact1) co-regulate the Wnt/Planar Cell Polarity (PCP) pathway during mammalian development.
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DOI：
10.4161/cib.26834
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发表时间：
2013-11-01
影响因子：
--
通讯作者：
Cheyette BN
中科院分区：
文献类型：
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作者：
Yang X;Fisher DA;Cheyette BN
我们以前报道，Sestd 1 KO表型模仿Dact 1 KO在小鼠中，与Sestd 1和Dact 1共同作用形成一个重要的功能复合物，调节Vangl 2在Wnt/平面细胞极性（PCP）途径的模型一致。在这里，我们表明，Dvl 2，Dact 1的结合伙伴，也形成复合物与Sestd 1，这样做独立于Dact 1和Vangl 2。在基于细胞的测定中，Sestd 1不改变Dvl 2对Wnt/β-连环蛋白信号传导途径的激活，而Dvl 2通过Dact 1和Sestd 1增强Rho家族GTP酶的激活，这与PCP途径中的作用一致。在小鼠中，尽管Dvl 2 KO在其他野生型背景中是隐性的，但它在Sestd 1或Dact 1 KO背景中导致显性胚胎致死。这种遗传协同作用与我们先前报道的Sestd 1和Dact 1 KO之间的上位性相反，并表明Dvl 2与Sestd 1/Dact 1在发育过程中PCP途径的调节中具有独立或半独立的功能。总之，Dvl 2，Sestd 1和Dact 1之间的生物化学和遗传相互作用，除了先前报道的这些相同的分子和Vangl 2之间的相互作用，表明所有这些基因产物可以形成复合物在一起，并在哺乳动物发育过程中调节PCP途径。然而，Sestd 1和Dact 1在Vangl 2的翻译后调节中具有密切相关的功能，这至少部分地不同于Dvl 2在该途径中的功能。
We previously reported that Sestd1 KO phenocopies Dact1 KO in mice, consistent with a model in which Sestd1 and Dact1 act together to form a crucial functional complex that regulates Vangl2 in the Wnt/Planar Cell Polarity (PCP) pathway. Here, we show that Dvl2, a binding partner of Dact1, also forms complexes with Sestd1, and does so independently of both Dact1 and Vangl2. In cell-based assays, whereas Sestd1 does not alter Dvl2 activation of the Wnt/β-catenin signaling pathway, Dvl2 enhances activation of Rho family GTPases by Dact1 and Sestd1, consistent with a role in the PCP pathway. In mice, although Dvl2 KO is recessive in an otherwise wild type background, it leads to dominant embryonic lethality in either the Sestd1 or Dact1 KO background. This genetic synergy stands in contrast to the epistasis we have previously reported between Sestd1 and Dact1 KO, and suggests independent or semi-independent functions for Dvl2 vs. Sestd1/Dact1 in the regulation of the PCP pathway during development. In conclusion, biochemical and genetic interactions between Dvl2, Sestd1, and Dact1, in addition to prior reported interactions between these same molecules and Vangl2, suggest that all these gene products can form complexes together and regulate the PCP pathway during mammalian development. However, Sestd1 and Dact1 have a closely allied function in the post-translational regulation of Vangl2 that is at least partially distinct from the functions of Dvl2 in this pathway.