在正常心脏流出道、耳蜗和神经管发育过程中,小鼠的散乱蛋白3与散乱蛋白1和2在冗余途径中发挥作用。
Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development.
作者信息
Etheridge S Leah, Ray Saugata, Li Shuangding, Hamblet Natasha S, Lijam Nardos, Tsang Michael, Greer Joy, Kardos Natalie, Wang Jianbo, Sussman Daniel J, Chen Ping, Wynshaw-Boris Anthony
机构信息
Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA.
出版信息
PLoS Genet. 2008 Nov;4(11):e1000259. doi: 10.1371/journal.pgen.1000259. Epub 2008 Nov 14.
Dishevelled (Dvl) proteins are important signaling components of both the canonical beta-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.
蓬乱蛋白(Dvl)是经典β-连环蛋白/Wnt信号通路和平面细胞极性(PCP)信号通路的重要信号转导成分。经典β-连环蛋白/Wnt信号通路控制细胞增殖和模式形成,而PCP信号通路则协调细胞层内的细胞极性,并指导汇聚延伸细胞(CE)运动,从而使组织变窄和伸长。已鉴定出三个哺乳动物Dvl基因,并且先前已确定Dvl1和Dvl2在发育中的作用。在此,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基因敲除小鼠在围产期死亡,伴有心脏流出道异常,包括右心室双出口和持续性动脉干。这些突变体在柯蒂氏器中还表现出立体纤毛方向错误的表型,当PCP成分Vangl2/Ltap(LtapLp/+)的单个等位基因进一步缺失时,该表型会增强。尽管在Dvl3基因敲除和LtapLp/+突变体中神经胚形成看起来正常,但Dvl3(+/-);LtapLp/+复合突变体表现出神经管闭合不完全。重要的是,我们表明Dvl3的许多作用也由Dvl1和Dvl2共同承担。在缺乏另一种Dvl的Dvl3突变体中观察到了更严重的表型,并且通过Dvl转基因在基因上增加Dvl剂量证明了Dvl之间能够相互补偿以实现正常发育。有趣的是,在双Dvl突变体中,整体经典Wnt信号传导在很大程度上未受影响,这表明低水平的Dvl足以产生功能性的经典Wnt信号。总之,我们证明Dvl3是心脏流出道发育所必需的,并描述了其在神经胚形成和耳蜗发育过程中在PCP信号通路中的重要性。最后,我们确定了三个Dvl在功能上具有冗余性的几个发育过程。