Unidirectional and stage-dependent roles of Notch1 in Wnt-responsive Lgr5+ cells during mouse inner ear development
Unidirectional and stage-dependent roles of Notch1 in Wnt-responsive Lgr5+ cells during mouse inner ear development
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在小鼠内耳发育过程中，Notch1 在 Wnt 反应性 Lgr5( ) 细胞中的单向和阶段依赖性作用。
DOI：
10.1007/s11684-019-0703-y
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发表时间：
2019-12-01
影响因子：
8.1
通讯作者：
Li, Wenyan
中科院分区：
文献类型：
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作者：
Jiang, Hui;Zeng, Shan;Li, Wenyan
在小鼠内耳发育过程中，WNT和Notch信号通路在决定前感觉域以及毛细胞和支持细胞的分化过程中起着至关重要的作用；然而，这两个信号通路在小鼠耳蜗组织中的关系仍然很不清楚。在此，我们基于Notch1在不同发育阶段对Wnt反应的Lgr5(+)前体细胞的双向调节作用，研究了Notch和Wnt信号之间的相互作用。我们发现从胚胎14.5天到胚胎18.5天，Lgr5(+)细胞中Notch1的表达下调可以促使静止的Lgr5(+)细胞重新进入细胞周期并分化为额外的HC，而Notch1的表达上调并不影响OGR5(+)细胞的增殖或分化。从E10.5到E14.5，对Lgr5(+)细胞Notch1的上调或下调均无影响。我们的结论是，Notch1在Wnt反应的Lgr5(+)细胞中的作用是单向的和阶段依赖的，Notch1在耳蜗分化过程中对Lgr5(+)前体细胞的激活起负调节作用。我们的发现提高了人们对Notch和Wnt信号在耳蜗发育过程中相互作用的理解。
Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells (HCs) and supporting cells during mouse inner ear development; however, the relationship between the two signaling pathways in the mouse cochlea remains largely unknown. Here, we investigated the interactions between Notch and Wnt signaling on the basis of the bidirectional regulation of Notch1 specifically in Wnt-responsive Lgr5(+) progenitors during different cochlear development stages. We found that the downregulation of Notch1 in Lgr5(+) cells from embryonic day (E) 14.5 to E18.5 can drive the quiescent Lgr5(+) cells to re-enter the cell cycle and differentiate into extra HCs, whereas the upregulation of Notch1 expression did not affect the proliferation or differentiation of otic progenitor cells. No effect was observed on the upregulation or downregulation of Notch1 in Lgr5(+) cells from E10.5 to E14.5. We concluded that the roles of Notch1 in Wnt-responsive Lgr5(+) cells are unidirectional and stage dependent and Notch1 serves as a negative regulator for Lgr5(+) progenitor activation during cochlear differentiation. Our findings improved the understanding of the interactions between Notch and Wnt signaling in cochlear development.