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Abstract：
Canonical Wnt signaling plays crucial roles during development and disease. How Wnt signaling is modulated in different in vivo contexts is currently not well understood. Here, we investigate the modulation of Wnt signaling in the posterior lateral line primordium (pLLP), a cohort of ~100 cells that collectively migrate along the trunk of the zebrafish embryo. The pLLP comprises proliferative progenitor cells and organized epithelial cells that will form the mechanosensory organs of the posterior lateral line. Wnt signaling is active in the leading progenitor zone of the pLLP and restricted from the trailing zone through expression of the secreted Wnt inhibitors dkk1b and dkk2. We have identified a zebrafish strain, krm1(nl10), which carries a mutation in the kremen1 gene, a non-obligate co-receptor for the Dkk family of proteins. Previous studies have shown that Kremen1 inhibits Wnt signaling by facilitating internalization of the Kremen1-Dkk-Lrp5/6 complex. Surprisingly, we found that disruption of Kremen1 in the pLLP exhibited molecular and cellular phenotypes associated with a decrease rather than overactivation of Wnt signaling. Transplantation of wild-type cells into the mutant primordia failed to rescue the krm1(nl10) phenotype, thus revealing that the effects of Kremen1 loss are non-cell-autonomous. Finally, ectopic expression of Dkk1b-mTangerine protein revealed larger spread of the fusion protein in the mutant primordia compared with the wild type. Based on our data, we propose a novel mechanism in which Kremen1 modulates Wnt activity by restricting the range of secreted Dkk proteins during collective cell migration in the pLLP.
摘要：
典型的Wnt信号在发育和疾病中起着至关重要的作用。目前还没有很好地理解在不同的体内环境中如何调节Wnt信号传导。这里,我们研究了后侧线原基（pLLP）中Wnt信号的调制，一组约100个细胞，它们沿着斑马鱼胚胎的树干共同迁移。pLLP包含增殖性祖细胞和有组织的上皮细胞,其将形成后外侧线的机械感觉器官。Wnt信号传导在pLLP的前导祖细胞区是活跃的,并且通过分泌的Wnt抑制剂dkk1b和dkk2的表达而被限制在尾随区。我们发现了一种斑马鱼，krm1(nl10),它在kremen1基因中携带突变，Dkk家族蛋白质的非专性共受体。先前的研究表明，Kremen1通过促进Kremen1-Dkk-Lrp5/6复合物的内化来抑制Wnt信号传导。令人惊讶的是,我们发现pLLP中Kremen1的破坏表现出与Wnt信号减少相关的分子和细胞表型，而不是过度激活。将野生型细胞移植到突变原基中未能挽救krm1（nl10）表型，从而揭示Kremen1损失的影响是非细胞自主的。最后,与野生型相比，Dkk1b-mTangerine蛋白的异位表达显示融合蛋白在突变原基中的传播更大。根据我们的数据,我们提出了一种新机制，其中Kremen1通过限制pLLP中集体细胞迁移过程中分泌的Dkk蛋白的范围来调节Wnt活性。
