ERK/MAPK 信号通过 Wnt 通路调节对肠道发育至关重要,Development

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ERK/MAPK 信号通过 Wnt 通路调节对肠道发育至关重要
Development ( IF 3.7 ) Pub Date : 2020-08-03 , DOI: 10.1242/dev.185678
Gaigai Wei ₁ , Na Gao ₁ , Jiwei Chen ₁ , Lingling Fan ₁ , Zhiyang Zeng ₁ , Ganglong Gao ₂ , Liang Li ₁ , Guojiu Fang ₂ , Kewen Hu ₁ , Xiufeng Pang ₁ , Heng-Yu Fan ₃ , Hans Clevers ₄ , Mingyao Liu ₁ , Xueli Zhang _{1,

2} , Dali Li ₁

Affiliation

摘要肠道干细胞 (ISC) 的稳态是由生态位因子和内在信号网络的协调维持的。在这里，我们发现胚胎阶段肠上皮细胞中 Erk1 和 Erk2 (Erk1/2) 的缺失导致细胞增殖和迁移、ISC 扩张和息肉样结构的形成意外增加，导致出生后死亡. 上皮细胞 Erk1/2 的缺乏导致分泌细胞分化缺陷以及间充质细胞增殖和成熟受损。删除 Erk1/2 通过细胞自主和非自主机制强烈激活 Wnt 信号。在上皮细胞中，Erk1/2 耗竭导致反馈调节丧失，导致 Ras/Raf 级联激活，从而激活 Akt 活性以刺激 mTor 和 Wnt/β-连环蛋白途径。此外，Erk1/2 缺陷降低了印度刺猬的水平和下游通路成分的表达，包括间充质 Bmp4——肠道中的 Wnt 抑制因子。雷帕霉素对 mTor 信号的抑制部分挽救了 Erk1/2 耗竭引起的肠道缺陷，并显着延长了突变小鼠的寿命。这些数据表明，Erk/Mapk 信号通过在肠道发育过程中协调上皮-间充质相互作用而起到 Wnt 信号传导的关键调节剂的作用。总结：Erk/MAPK 信号通过细胞自主和非自主机制调节 Wnt 信号通路在肠道发育过程中发挥关键作用。Erk1/2 缺陷降低了印度刺猬的水平和下游通路成分的表达，包括间充质 Bmp4——肠道中的 Wnt 抑制因子。雷帕霉素对 mTor 信号的抑制部分挽救了 Erk1/2 耗竭引起的肠道缺陷，并显着延长了突变小鼠的寿命。这些数据表明，Erk/Mapk 信号通过在肠道发育过程中协调上皮-间充质相互作用而起到 Wnt 信号传导的关键调节剂的作用。总结：Erk/MAPK 信号通过细胞自主和非自主机制调节 Wnt 信号通路在肠道发育过程中发挥关键作用。Erk1/2 缺陷降低了印度刺猬的水平和下游通路成分的表达，包括间充质 Bmp4——肠道中的 Wnt 抑制因子。雷帕霉素对 mTor 信号的抑制部分挽救了 Erk1/2 耗竭引起的肠道缺陷，并显着延长了突变小鼠的寿命。这些数据表明，Erk/Mapk 信号通过在肠道发育过程中协调上皮-间充质相互作用而起到 Wnt 信号传导的关键调节剂的作用。总结：Erk/MAPK 信号通过细胞自主和非自主机制调节 Wnt 信号通路在肠道发育过程中发挥关键作用。雷帕霉素对 mTor 信号的抑制部分挽救了 Erk1/2 耗竭引起的肠道缺陷，并显着延长了突变小鼠的寿命。这些数据表明，Erk/Mapk 信号通过在肠道发育过程中协调上皮-间充质相互作用而起到 Wnt 信号传导的关键调节剂的作用。总结：Erk/MAPK 信号通过细胞自主和非自主机制调节 Wnt 信号通路在肠道发育过程中发挥关键作用。雷帕霉素对 mTor 信号的抑制部分挽救了 Erk1/2 耗竭引起的肠道缺陷，并显着延长了突变小鼠的寿命。这些数据表明，Erk/Mapk 信号通过在肠道发育过程中协调上皮-间充质相互作用而起到 Wnt 信号传导的关键调节剂的作用。总结：Erk/MAPK 信号通过细胞自主和非自主机制调节 Wnt 信号通路在肠道发育过程中发挥关键作用。这些数据表明，Erk/Mapk 信号通过在肠道发育过程中协调上皮-间充质相互作用而起到 Wnt 信号传导的关键调节剂的作用。总结：Erk/MAPK 信号通过细胞自主和非自主机制调节 Wnt 信号通路在肠道发育过程中发挥关键作用。这些数据表明，Erk/Mapk 信号通过在肠道发育过程中协调上皮-间充质相互作用而起到 Wnt 信号传导的关键调节剂的作用。总结：Erk/MAPK 信号通过细胞自主和非自主机制调节 Wnt 信号通路在肠道发育过程中发挥关键作用。

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ERK/MAPK signaling is essential for intestinal development through Wnt pathway modulation

ABSTRACT Homeostasis of intestinal stem cells (ISCs) is maintained by the orchestration of niche factors and intrinsic signaling networks. Here, we have found that deletion of Erk1 and Erk2 (Erk1/2) in intestinal epithelial cells at embryonic stages resulted in an unexpected increase in cell proliferation and migration, expansion of ISCs, and formation of polyp-like structures, leading to postnatal death. Deficiency of epithelial Erk1/2 results in defects in secretory cell differentiation as well as impaired mesenchymal cell proliferation and maturation. Deletion of Erk1/2 strongly activated Wnt signaling through both cell-autonomous and non-autonomous mechanisms. In epithelial cells, Erk1/2 depletion resulted in loss of feedback regulation, leading to Ras/Raf cascade activation that transactivated Akt activity to stimulate the mTor and Wnt/β-catenin pathways. Moreover, Erk1/2 deficiency reduced the levels of Indian hedgehog and the expression of downstream pathway components, including mesenchymal Bmp4 – a Wnt suppressor in intestines. Inhibition of mTor signaling by rapamycin partially rescued Erk1/2 depletion-induced intestinal defects and significantly prolonged the lifespan of mutant mice. These data demonstrate that Erk/Mapk signaling functions as a key modulator of Wnt signaling through coordination of epithelial-mesenchymal interactions during intestinal development. Summary: Erk/MAPK signaling plays a crucial role during intestinal development through modulation of the Wnt signaling pathway by both cell-autonomous and non-autonomous mechanisms.

更新日期：2020-08-03

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