Deletion of the Dishevelled family of genes disrupts anterior-posterior axis specification and selectively prevents mesoderm differentiation.
Deletion of the Dishevelled family of genes disrupts anterior-posterior axis specification and selectively prevents mesoderm differentiation.
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DOI：
10.1016/j.ydbio.2020.05.010
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发表时间：
2020-08-15
影响因子：
2.7
通讯作者：
Wynshaw-Boris A
中科院分区：
文献类型：
--
作者：
Ngo J;Hashimoto M;Hamada H;Wynshaw-Boris A
Dishevelled蛋白参与了经典Wnt/β-catenin和非经典Wnt/planar cell polarity（PCP）信号通路，调控胚胎发育过程中的许多关键发育过程。在这里，我们通过靶向整个Dishevelled基因家族（Dvl 1，Dvl 2和Dvl 3）来破坏经典和非经典Wnt通路，以研究它们在早期胚胎中的功能作用。我们在Dvl 1 +/−; Dvl 2 −/−; Dvl 3 −/−胚胎中发现了前后轴特化和中胚层图案化的几个缺陷。所有三个Dvl基因中的纯合缺失（Dvl TKO）导致远端内脏内胚层迁移的缺陷和诱导中胚层形成的完全失败。为了鉴定导致原肠胚形成之前的发育过程中的缺陷的潜在机制，我们产生了Dvl TKO小鼠胚胎干细胞（mESC），并将这些细胞与野生型（WT）mESC在生殖谱系分化成3D胚状体（EB）期间的转录谱进行了比较。虽然Dvl TKO mESC显示出与WT mESC相似的形态、自我更新特性和较小的转录变异，但我们鉴定了Dvl TKO EB在分化期间在参与前后模式特化、原肠胚形成诱导、间充质形态发生和中胚层衍生的组织发育的许多基因中的主要转录失调。Dvl的缺乏导致BMP信号传导基因的特异性下调。此外，经典Wnt、BMP和Nodal信号传导的外源性激活都不能挽救Dvl TKO EB中的中胚层缺陷。此外，在Dvl TKO EB中，在不存在中胚层的情况下促进内胚层分化，而外胚层分化的抑制被延迟。总体而言，我们证明Dvls是维持mESC自我更新的关键，但在分化过程中对调节关键发育信号通路以促进适当的轴特化和中胚层形成至关重要。
The Dishevelled proteins transduce both canonical Wnt/β-catenin and non-canonical Wnt/planar cell polarity (PCP) signaling pathways to regulate many key developmental processes during embryogenesis. Here, we disrupt both canonical and non-canonical Wnt pathways by targeting the entire Dishevelled family of genes (Dvl1, Dvl2, and Dvl3) to investigate their functional roles in the early embryo. We identified several defects in anterior-posterior axis specification and mesoderm patterning in Dvl1+/−; Dvl2−/−; Dvl3−/− embryos. Homozygous deletions in all three Dvl genes (Dvl TKO) resulted in defects in distal visceral endoderm migration and a complete failure to induce mesoderm formation. To identify potential mechanisms that lead to the defects in the developmental processes preceding gastrulation, we generated Dvl TKO mouse embryonic stem cells (mESCs) and compared the transcriptional profile of these cells with wild-type (WT) mESCs during germ lineage differentiation into 3D embryoid bodies (EBs). While the Dvl TKO mESCs displayed similar morphology, self-renewal properties, and minor transcriptional variation from WT mESCs, we identified major transcriptional dysregulation in the Dvl TKO EBs during differentiation in a number of genes involved in anterior-posterior pattern specification, gastrulation induction, mesenchyme morphogenesis, and mesoderm-derived tissue development. The absence of the Dvls leads to specific down-regulation of BMP signaling genes. Furthermore, exogenous activation of canonical Wnt, BMP, and Nodal signaling all fail to rescue the mesodermal defects in the Dvl TKO EBs. Moreover, endoderm differentiation was promoted in the absence of mesoderm in the Dvl TKO EBs, while the suppression of ectoderm differentiation was delayed. Overall, we demonstrate that the Dvls are dispensable for maintaining self-renewal in mESCs but are critical during differentiation to regulate key developmental signaling pathways to promote proper axis specification and mesoderm formation.
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DOI：
10.1242/dev.085654
发表时间：
2013-03
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Faunes F;Hayward P;Descalzo SM;Chatterjee SS;Balayo T;Trott J;Christoforou A;Ferrer-Vaquer A;Hadjantonakis AK;Dasgupta R;Arias AM
通讯作者：
Arias AM
影响因子：
2.7
作者：
Hao, J;Li, TG;Zhao, GQ
通讯作者：
Zhao, GQ
影响因子：
4.6
作者：
Engert, Silvia;Burtscher, Ingo;Lickert, Heiko
通讯作者：
Lickert, Heiko
影响因子：
4.5
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
通讯作者：
Wynshaw-Boris A
DOI：
10.1073/pnas.1006437108
发表时间：
2011-08-02
影响因子：
11.1
作者：
Barrott, Jared J.;Cash, Gabriela M.;Murtaugh, L. Charles
通讯作者：
Murtaugh, L. Charles