Wnt/β-catenin interacts with the FGF pathway to promote proliferation and regenerative cell proliferation in the zebrafish lateral line neuromast
Wnt/β-catenin interacts with the FGF pathway to promote proliferation and regenerative cell proliferation in the zebrafish lateral line neuromast
复制标题
Wnt/β-连环蛋白与 FGF 通路相互作用促进斑马鱼侧线神经丘增殖和再生细胞增殖
DOI：
10.1038/s12276-019-0247-x
复制
发表时间：
2019-05-23
影响因子：
12.8
通讯作者：
Li, Huawei
中科院分区：
文献类型：
--
作者：
Tang, Dongmei;He, Yingzi;Li, Huawei
Wnt和FGF是在多种器官中发现的高度保守的信号通路，并已被确定为听觉器官发育的重要调节因子。在本研究中，我们利用斑马鱼侧线系统研究Wnt和FGF通路在调节祖细胞增殖和再生细胞增殖中的协同作用。我们发现 Wnt 信号传导的激活会诱导细胞增殖，并增加发育和再生神经丘中毛细胞的数量。我们进一步证明，FGF 信号传导在 Wnt 调节的增殖中至关重要，抑制 FGF 消除了 Wnt 刺激介导的细胞增殖作用，而用碱性成纤维细胞生长因子 (bFGF) 激活 FGF 信号传导则在缺乏 Wnt 活性的情况下部分挽救了增殖失败和毛细胞缺陷。整体原位杂交分析表明，用 Wnt 通路诱导剂 BIO 处理后，神经丘中几个 FGF 通路基因（包括 pea3 和 fgfr1）的表达增加。有趣的是，当 SU5402 用于抑制 FGF 信号传导时，神经丘细胞表达的 FGF 受体基因 fgfr1 水平要低得多，但产生的 Wnt 靶基因水平升高，包括 ctnnb1、ctnnb2 和 tcf712，而 bFGF 处理不会导致这些基因的表达发生变化，表明 fgfr1 可能在增殖过程中限制神经丘中的 Wnt 信号传导。总之，我们的分析表明，Wnt 和 FGF 通路紧密整合，在斑马鱼神经丘中新霉素诱导损伤后的早期神经丘发育和再生细胞增殖过程中调节祖细胞的增殖。
Wnt and FGF are highly conserved signaling pathways found in various organs and have been identified as important regulators of auditory organ development. In this study, we used the zebrafish lateral line system to study the cooperative roles of the Wnt and FGF pathways in regulating progenitor cell proliferation and regenerative cell proliferation. We found that activation of Wnt signaling induced cell proliferation and increased the number of hair cells in both developing and regenerating neuromasts. We further demonstrated that FGF signaling was critically involved in Wnt-regulated proliferation, and inhibition of FGF abolished the Wnt stimulation-mediated effects on cell proliferation, while activating FGF signaling with basic fibroblast growth factor (bFGF) led to a partial rescue of the proliferative failure and hair cell defects in the absence of Wnt activity. Whole-mount in situ hybridization analysis showed that the expression of several FGF pathway genes, including pea3 and fgfr1, was increased in neuromasts after treatment with the Wnt pathway inducer BIO. Interestingly, when SU5402 was used to inhibit FGF signaling, neuromast cells expressed much lower levels of the FGF receptor gene, fgfr1, but produced increased levels of Wnt target genes, including ctnnb1, ctnnb2, and tcf712, while bFGF treatment produced no alterations in the expression of those genes, suggesting that fgfr1 might restrict Wnt signaling in neuromasts during proliferation. In summary, our analysis demonstrates that both the Wnt and FGF pathways are tightly integrated to modulate the proliferation of progenitor cells during early neuromast development and regenerative cell proliferation after neomycin-induced injury in the zebrafish neuromast.