Wnt/β-catenin signaling directly regulates Foxj1 expression and ciliogenesis in zebrafish Kupffer's vesicle
Wnt/β-catenin signaling directly regulates Foxj1 expression and ciliogenesis in zebrafish Kupffer's vesicle
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DOI：
10.1242/dev.071746
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发表时间：
2012-02-01
期刊：
影响因子：
4.6
通讯作者：
Lin, Xueying
中科院分区：
文献类型：
--
作者：
Caron, Alissa;Xu, Xiaolei;Lin, Xueying
纤毛对正常发育至关重要。纤毛的组成和组装已经被很好地表征，但控制纤毛发生的信号传导和转录途径仍然缺乏研究。在这里，我们报道了Wnt/ β -catenin信号直接调节斑马鱼Kupffer囊泡（KV）中纤毛生成转录因子foxj1a的表达和纤毛发生。我们发现Wnt信号暂时和KV细胞自主地控制左右（LR）轴的确定和纤毛发生。具体而言，Wnt信号的减少导致LR模式的破坏，纤毛变短和减少，纤毛运动性丧失和foxj1a表达下调。然而，这些表型可以通过以kv为靶点的foxj1a过表达来挽救。与之前被认为与纤毛发生有关的FGF通路相比，我们的上位性研究表明Wnt信号在KV中更下游的作用是调节foxj1a表达和纤毛发生。重要的是，增强子分析显示，foxj1a的kv特异性表达需要假定的Lef1/Tcf结合位点的存在，这表明Wnt信号直接激活foxj1a的转录。我们还发现，Wnt信号受损可导致肾囊肿和耳石组织紊乱，这可归因于foxj1表达缺失和发育中的肾原管和耳小泡的纤毛发生中断。总之，我们的数据揭示了Wnt/ β -catenin信号在纤毛发生上游的新作用，这可能是一种超越KV的一般发育机制。此外，我们的研究结果还提出了一种假设，即Wnt/ β -catenin通路的某些发育效应是由于Foxj1的激活和纤毛的形成。
Cilia are essential for normal development. The composition and assembly of cilia has been well characterized, but the signaling and transcriptional pathways that govern ciliogenesis remain poorly studied. Here, we report that Wnt/beta-catenin signaling directly regulates ciliogenic transcription factor foxj1a expression and ciliogenesis in zebrafish Kupffer's vesicle (KV). We show that Wnt signaling acts temporally and KV cell-autonomously to control left-right (LR) axis determination and ciliogenesis. Specifically, reduction of Wnt signaling leads to a disruption of LR patterning, shorter and fewer cilia, a loss of cilia motility and a downregulation of foxj1a expression. However, these phenotypes can be rescued by KV-targeted overexpression of foxj1a. In comparison to the FGF pathway that has been previously implicated in the control of ciliogenesis, our epistatic studies suggest a more downstream function of Wnt signaling in the regulation of foxj1a expression and ciliogenesis in KV. Importantly, enhancer analysis reveals that KV-specific expression of foxj1a requires the presence of putative Lef1/Tcf binding sites, indicating that Wnt signaling activates foxj1a transcription directly. We also find that impaired Wnt signaling leads to kidney cysts and otolith disorganization, which can be attributed to a loss of foxj1 expression and disrupted ciliogenesis in the developing pronephric ducts and otic vesicles. Together, our data reveal a novel role of Wnt/beta-catenin signaling upstream of ciliogenesis, which might be a general developmental mechanism beyond KV. Moreover, our results also prompt a hypothesis that certain developmental effects of the Wnt/beta-catenin pathway are due to the activation of Foxj1 and cilia formation.