Co-regulation of the Notch and Wnt signaling pathways promotes supporting cell proliferation and hair cell regeneration in mouse utricles.
Co-regulation of the Notch and Wnt signaling pathways promotes supporting cell proliferation and hair cell regeneration in mouse utricles.
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Notch 和 Wnt 信号通路的共同调节可促进小鼠椭圆囊中的细胞增殖和毛细胞再生。
DOI：
10.1038/srep29418
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发表时间：
2016-07-20
影响因子：
4.6
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Wu J;Li W;Lin C;Chen Y;Cheng C;Sun S;Tang M;Chai R;Li H
这项工作试图确定Notch和Wnt信号通路在调节支持细胞(SC)增殖和毛细胞(HC)再生中的串扰。培养小鼠出生后3天和60天的卵泡，用庆大霉素损伤卵泡细胞，用γ分泌酶抑制剂DAPT抑制Notch通路，用Wnt激动剂QS11激活Wnt通路。我们还利用Sox2-Creer、Notch1-Flox(外显子1)和Catnb-Flox(外显子3)转基因小鼠敲除了Sox2+SCs中的Notch通路并激活了Wnt通路。单独的缺口抑制增加了未损伤和损伤的椭圆囊中的SC增殖和HC数量。WNT单独激活可促进SC增殖，但对HC数量无明显影响。在这里，我们证明了Notch抑制和Wnt激活在调控SC增殖和HC再生中的累积效应。同时，抑制Notch和过表达Wnt导致SC的增殖和更多的HC数量比单独操作任何一条途径都要大。在转基因小鼠中也观察到了类似的结果。本研究提示，Notch抑制和Wnt激活联合应用能显著促进小鼠卵圆囊内SC的增殖并增加再生的HC数量。
This work sought to determine the crosstalk between the Notch and Wnt signaling pathways in regulating supporting cell (SC) proliferation and hair cell (HC) regeneration in mouse utricles. We cultured postnatal day (P)3 and P60 mouse utricles, damaged the HCs with gentamicin, and treated the utricles with the γ-secretase inhibitor DAPT to inhibit the Notch pathway and with the Wnt agonist QS11 to active the Wnt pathway. We also used Sox2-CreER, Notch1-flox (exon 1), and Catnb-flox (exon 3) transgenic mice to knock out the Notch pathway and activate the Wnt pathway in Sox2+ SCs. Notch inhibition alone increased SC proliferation and HC number in both undamaged and damaged utricles. Wnt activation alone promoted SC proliferation, but the HC number was not significantly increased. Here we demonstrated the cumulative effects of Notch inhibition and Wnt activation in regulating SC proliferation and HC regeneration. Simultaneously inhibiting Notch and overexpressing Wnt led to significantly greater SC proliferation and greater numbers of HCs than manipulating either pathway alone. Similar results were observed in the transgenic mice. This study suggests that the combination of Notch inhibition and Wnt activation can significantly promote SC proliferation and increase the number of regenerated HCs in mouse utricle.