Rab8a vesicles regulate Wnt ligand delivery and Paneth cell maturation at the intestinal stem cell niche.
Rab8a vesicles regulate Wnt ligand delivery and Paneth cell maturation at the intestinal stem cell niche.
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DOI：
10.1242/dev.121046
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发表时间：
2015-06-15
期刊：
影响因子：
--
通讯作者：
Gao N
中科院分区：
文献类型：
--
作者：
Das S;Yu S;Sakamori R;Vedula P;Feng Q;Flores J;Hoffman A;Fu J;Stypulkowski E;Rodriguez A;Dobrowolski R;Harada A;Hsu W;Bonder EM;Verzi MP;Gao N
干细胞和壁龛支持细胞之间的通讯维持了成体组织的动态平衡。WNT信号是干细胞生态位的重要调节因子，但WNT配体在这一区域的传递机制尚未得到充分研究。我们发现Wnt的分泌部分依赖于Rab8a介导的Wnt特异性跨膜转运蛋白Gpr177(Wnless)的顺行转运。Gpr177与Rab8a结合，其耗尽会影响Gpr177的流量，从而削弱多个WnT的分泌。对Rab8a基因敲除小鼠肠道隐窝中通用Wnt/β-catenin靶标的分析表明，信号活性降低；潘氏细胞--一种依赖Wnt的细胞类型--的成熟受到严重影响。Rab8a基因敲除的隐窝在体内显示Lgr5+和Hopx+细胞的扩张。然而，在体外，基因敲除的肠样显示出显著减弱的生长，这可以通过外源WNTS或GSK3β抑制剂部分恢复。免疫金标记法和表面蛋白分离证实，GPR177在Rab8a基因敲除的Paneth细胞和成纤维细胞中的质膜定位减少。在外源WNTS的刺激下，Rab8a缺陷细胞表现出配体诱导的LRP6磷酸化和转录报告激活。因此，Rab8a控制着Wnt在生产细胞中的传递，对Paneth细胞的成熟至关重要。我们的数据突出了由于干细胞生态位信号耗尽而引起的压力所产生的深刻的组织可塑性。摘要：在成熟的小鼠Paneth细胞中，Wnt的分泌部分依赖于Rab8a介导的Gpr177的顺行运输。Rab8a是Paneth细胞成熟所必需的。
Communication between stem and niche supporting cells maintains the homeostasis of adult tissues. Wnt signaling is a crucial regulator of the stem cell niche, but the mechanism that governs Wnt ligand delivery in this compartment has not been fully investigated. We identified that Wnt secretion is partly dependent on Rab8a-mediated anterograde transport of Gpr177 (wntless), a Wnt-specific transmembrane transporter. Gpr177 binds to Rab8a, depletion of which compromises Gpr177 traffic, thereby weakening the secretion of multiple Wnts. Analyses of generic Wnt/β-catenin targets in Rab8a knockout mouse intestinal crypts indicate reduced signaling activities; maturation of Paneth cells – a Wnt-dependent cell type – is severely affected. Rab8a knockout crypts show an expansion of Lgr5+ and Hopx+ cells in vivo. However, in vitro, the knockout enteroids exhibit significantly weakened growth that can be partly restored by exogenous Wnts or Gsk3β inhibitors. Immunogold labeling and surface protein isolation identified decreased plasma membrane localization of Gpr177 in Rab8a knockout Paneth cells and fibroblasts. Upon stimulation by exogenous Wnts, Rab8a-deficient cells show ligand-induced Lrp6 phosphorylation and transcriptional reporter activation. Rab8a thus controls Wnt delivery in producing cells and is crucial for Paneth cell maturation. Our data highlight the profound tissue plasticity that occurs in response to stress induced by depletion of a stem cell niche signal. Summary: In maturing mouse Paneth cells, Wnt secretion is partly dependent on a Rab8a-mediated anterograde transport of Gpr177. Rab8a is required for Paneth cell maturation.
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