Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development.
Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development.
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DOI：
10.1371/journal.pgen.1000259
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发表时间：
2008-11
期刊：
影响因子：
4.5
通讯作者：
Wynshaw-Boris A
中科院分区：
文献类型：
--
作者：
Etheridge SL;Ray S;Li S;Hamblet NS;Lijam N;Tsang M;Greer J;Kardos N;Wang J;Sussman DJ;Chen P;Wynshaw-Boris A
disheveled （Dvl）蛋白是规范β-catenin/Wnt通路和平面细胞极性（PCP）通路的重要信号成分，前者控制细胞增殖和成图化，后者协调细胞片内的细胞极性，并指导产生组织变窄和伸长的趋同延伸细胞（CE）运动。三个哺乳动物的Dvl基因已经被鉴定出来，并且Dvl1和Dvl2在发育中的作用也已经被确定。在这里，我们确定了Dvl3在发育中的功能，并提供了三种小鼠dvl之间功能冗余的证据。Dvl3 - / -小鼠死于围产期心脏流出道异常，包括双出口右心室和持续性动脉主干病变。这些突变体在Corti器官中也表现出定向错误的直立纤毛，这种表型随着PCP组分Vangl2/Ltap （LtapLp/+）的单个等位基因的额外丢失而增强。尽管在Dvl3−/−和LtapLp/+突变体中，神经系统发育正常，但Dvl3 +/−；LtapLp/+组合突变体表现为神经管闭合不完全。重要的是，我们证明了Dvl1和Dvl2也共享Dvl3的许多角色。在缺乏另一种Dvl的Dvl3突变体中观察到更严重的表型，并且通过Dvl转基因增加Dvl剂量表明Dvl能够相互补偿以实现正常发育。有趣的是，在双Dvl突变体中，全球典型Wnt信号在很大程度上未受影响，这表明低Dvl水平足以产生功能性典型Wnt信号。总之，我们证明了Dvl3是心脏流出道发育所必需的，并描述了它在神经和耳蜗发育过程中PCP通路中的重要性。最后，我们建立了几个发育过程，其中三个dvl是功能冗余的。多基因家族在哺乳动物中很常见，由一组具有共同核苷酸序列的非常相似的基因组成。每个家庭成员可能在不同的地方表达，履行不同的职能。或者，这些基因可能有冗余的功能，但剂量要求不同。哺乳动物共有三个disheveled （Dvl）家族成员，虽然Dvl1和Dvl2的作用已经被描述过，但Dvl3的功能仍然难以捉摸。在这里，我们发现小鼠缺乏Dvl3会影响心脏、神经管和内耳的形成。我们进一步表明，当小鼠缺乏一个以上的Dvl家族成员时，这些组织中的缺陷要严重得多，这表明这些基因具有冗余功能。每1000个活产儿中约有75人患有先天性心脏病，其中约30%的疾病是由于流出道的破坏造成的，该区域在缺乏Dvl基因的小鼠中受到影响。神经管缺陷，类似于在Dvl突变体中观察到的缺陷，在人类中也很常见。这里描述的动物模型为阐明这些异常的遗传机制提供了有用的工具，并可能在未来提供治疗这些疾病的新方法。
Dishevelled (Dvl) proteins are important signaling components of both the canonical β-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP) pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE) movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, we identify the functions of Dvl3 in development and provide evidence of functional redundancy among the three murine Dvls. Dvl3 −/− mice died perinatally with cardiac outflow tract abnormalities, including double outlet right ventricle and persistent truncus arteriosis. These mutants also displayed a misorientated stereocilia in the organ of Corti, a phenotype that was enhanced with the additional loss of a single allele of the PCP component Vangl2/Ltap (LtapLp/+). Although neurulation appeared normal in both Dvl3 −/− and LtapLp/+ mutants, Dvl3 +/−;LtapLp/+ combined mutants displayed incomplete neural tube closure. Importantly, we show that many of the roles of Dvl3 are also shared by Dvl1 and Dvl2. More severe phenotypes were observed in Dvl3 mutants with the deficiency of another Dvl, and increasing Dvl dosage genetically with Dvl transgenes demonstrated the ability of Dvls to compensate for each other to enable normal development. Interestingly, global canonical Wnt signaling appeared largely unaffected in the double Dvl mutants, suggesting that low Dvl levels are sufficient for functional canonical Wnt signals. In summary, we demonstrate that Dvl3 is required for cardiac outflow tract development and describe its importance in the PCP pathway during neurulation and cochlea development. Finally, we establish several developmental processes in which the three Dvls are functionally redundant. Multi-gene families, comprising a set of very similar genes with shared nucleotide sequences, are common in mammals. Individual family members may be expressed in different places and perform separate functions. Alternatively, the genes may have redundant functions, but distinct dosage requirements. Mammals share three Dishevelled (Dvl) family members and while the roles of Dvl1 and Dvl2 have been described previously, the functions of Dvl3 have remained elusive. Here, we show that the lack of Dvl3 in mice affects the formation of the heart, neural tube, and inner ear. We further show that the defects in these tissues are much more severe when the mice are deficient in more than one Dvl family member, indicating redundant functions for these genes. Congenital heart disease affects approximately 75 in every 1,000 live human births, and approximately 30% of these diseases are due to disruptions in the outflow tract, the region affected in mice lacking Dvl genes. Neural tube defects, similar to those observed in the Dvl mutants, are also common in humans. The animal models described here provide useful tools to elucidate the genetic mechanisms that underlie these abnormalities and may provide novel ways of treating these disorders in the future.
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影响因子：
2.6
作者：
Klingensmith, J;Yang, Y;Sussman, DJ
通讯作者：
Sussman, DJ
DOI：
10.1073/pnas.0704044104
发表时间：
2007-06-26
影响因子：
11.1
作者：
Kwon, Chulan;Arnold, Joshua;Srivastava, Deepak
通讯作者：
Srivastava, Deepak
DOI：
10.1073/pnas.0402802101
发表时间：
2004-06-22
影响因子：
11.1
作者：
Guo, N;Hawkins, C;Nathans, J
通讯作者：
Nathans, J
影响因子：
20.1
作者：
Henderson, DJ;Conway, SJ;Copp, AJ
通讯作者：
Copp, AJ
影响因子：
2.1
作者：
Hutson, Mary Redmond;Kirby, Margaret L.
通讯作者：
Kirby, Margaret L.