Wntless/GPR177对小鼠原肠发生和心脏发育至关重要（英文）

Requirement of Wntless/GPR177 in Mouse Gastrulation and Heart Development

小鼠早期胚胎发育包含原肠运动和器官发生等重要发育过程,这些过程受多种信号通路调控,其中有Wnt、BMP、Nodal、FGF等信号通路,它们之间进行精细严密的协调,保证胚胎发育的正确进行。β-联蛋白作为Wnt配体的共同下游信号分子,在小鼠原肠运动和器官发生中发挥至关重要的作用。Wntless/GPR177在以前的研究中已被报道参与调节Wnt配体的成熟、分选和分泌等,小鼠全身剔除Wntless(Wls)将严重影响胚胎体轴形成。在该研究中,Wls被特异性地在上胚层、心血管中胚层和心肌祖细胞中剔除,以探索Wls如何参与到小鼠原肠运动和心血管发育中。我们发现,在上胚层剔除Wls后,明显阻断了上皮-间充质转化过程,这是中胚层迁移中的关键步骤。在Wls条件性剔除的上胚层中,β-联蛋白表达模式发生变化,表达水平明显下降;E-钙黏着蛋白和N-钙黏着蛋白明显上升。此外,被剔除Wls的上胚层中,细胞凋亡明显增加。不论是在心脏中胚层还是在心脏前体细胞中,剔除Wls都导致严重的心血管发育缺陷和胚胎死亡,证明Wls对心脏发育同样十分重要。这些研究结果证明,Wntless在小鼠原肠运动和心脏发育中均发挥十分重要的作用。

Mouse early embryonic development including gastrulation and organogenesis requires the elegantly orchestrated actions of several essential signaling molecules of Wnt,BMP,Nodal and FGF.A panel of Wnt ligands and their common downstream target,β-catenin,plays a pivotal role in mouse gastrulation and organ development.Wntless/GPR177 has been reported to be involved in regulating the maturation,sorting and secretion of Wnt ligands and global deletion of Wntless(Wls)impairs body axis formation.In this study,Wls was conditionally removed from the epiblast and cardiac mesoderm and progenitors to investigate how Wls is involved in mouse gastrulation and heart development.We found that the deletion of Wls profoundly hindered the epithelial to mesenchymal transition(EMT)process required for mesoderm migration.Whileβ-catenin protein level was greatly reduced,the levels of both E-cadherin and N-cadherin were substantially enhanced in Wls-deleted epiblast.Furthermore,a disrupted cell apoptosis was observed in the Wls-defective epiblast.In addition,Wls is essential for heart development as deletion of Wls either in the cardiac progenitor or mesoderm resulted in severe heart defects and embryonic lethality.Thus,our study has demonstrated the critical function of Wls in gastrulation and heart development.