Wnt/β-catenin signalling regulates Sox17 expression and is essential for organizer and endoderm formation in the mouse
Wnt/β-catenin signalling regulates Sox17 expression and is essential for organizer and endoderm formation in the mouse
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DOI：
10.1242/dev.088765
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发表时间：
2013-08-01
期刊：
影响因子：
4.6
通讯作者：
Lickert, Heiko
中科院分区：
文献类型：
--
作者：
Engert, Silvia;Burtscher, Ingo;Lickert, Heiko
几个信号级联涉及的三个主要胚层的形成和图案，但其精确的时间-空间模式的行动在祖先人口仍然不确定。我们已经在Sox 17阳性的胚胎和胚胎外内胚层以及血管内皮祖细胞中使用了小鼠β-连环蛋白的条件性基因缺失，以解决经典Wnt信号传导在细胞谱系形成和模式化中的功能。条件突变体不能形成前脑结构，并表现出后体轴截断，而最初的血管形成似乎正常。四倍体拯救实验表明，前内脏内胚层中β-连环蛋白的缺乏导致头部组织者形成缺陷。定形内胚层（DE）中的Sox 17谱系追踪显示了中肠和后肠形成中对β-连环蛋白的细胞自主需求。令人惊讶的是，中肠和后肠缺陷四倍体嵌合体中的野生型后内脏内胚层（PVE）挽救了后体轴截短，表明PVE对尾组织者形成很重要。在内脏内胚层和DE谱系中β-连环蛋白丢失后，而不是在血管内皮谱系中，Sox 17表达不被维持，表明通过典型Wnt信号传导的下游调节。引人注目的是，Tcf 4/β-连环蛋白反式激活复合物积累的Sox 17顺式调控元件，特别是在胚胎干细胞分化系统中的内胚层诱导。总之，这些结果表明，Wnt/β-连环蛋白信号通路调节Sox 17表达内脏内胚层模式和DE的形成，并提供了第一个功能的证据，PVE是必要的原肠胚组织者基因诱导和后轴的发展。
Several signalling cascades are implicated in the formation and patterning of the three principal germ layers, but their precise temporal-spatial mode of action in progenitor populations remains undefined. We have used conditional gene deletion of mouse beta-catenin in Sox17-positive embryonic and extra-embryonic endoderm as well as vascular endothelial progenitors to address the function of canonical Wnt signalling in cell lineage formation and patterning. Conditional mutants fail to form anterior brain structures and exhibit posterior body axis truncations, whereas initial blood vessel formation appears normal. Tetraploid rescue experiments reveal that lack of beta-catenin in the anterior visceral endoderm results in defects in head organizer formation. Sox17 lineage tracing in the definitive endoderm (DE) shows a cell-autonomous requirement for beta-catenin in midgut and hindgut formation. Surprisingly, wildtype posterior visceral endoderm (PVE) in midgut-and hindgut-deficient tetraploid chimera rescues the posterior body axis truncation, indicating that the PVE is important for tail organizer formation. Upon loss of beta-catenin in the visceral endoderm and DE lineages, but not in the vascular endothelial lineage, Sox17 expression is not maintained, suggesting downstream regulation by canonical Wnt signalling. Strikingly, Tcf4/beta-catenin transactivation complexes accumulated on Sox17 cis-regulatory elements specifically upon endoderm induction in an embryonic stem cell differentiation system. Together, these results indicate that the Wnt/beta-catenin signalling pathway regulates Sox17 expression for visceral endoderm pattering and DE formation and provide the first functional evidence that the PVE is necessary for gastrula organizer gene induction and posterior axis development.