文章基本信息

标题：Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway
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作者：Wenyan Li ; Jingfang Wu ; Jianming Yang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：166-171
DOI：10.1073/pnas.1415901112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNotch signaling is known as a fundamental pathway that regulates the cell-fate determination in the inner ear. In present study, we show that Notch signaling also acts as a negative regulator that inhibits the proliferation of Lgr5+ progenitors and maintains the homeostasis of cochlear sensory epithelium on cell numbers. More importantly, to our knowledge we provide the first piece of evidence illustrating the interaction between Notch and Wnt in the postal mouse cochlea: Notch inhibition activates the canonical Wnt pathway in the progenitor cells, which leads to mitotic generation of hair cells; but Notch inhibition induced direct supporting cell-to-hair cell transdifferentiation that is Wnt-independent. Our findings may be useful in dissecting the mechanisms regulating mammalian inner ear proliferation and hair cell generation. The activation of cochlear progenitor cells is a promising approach for hair cell (HC) regeneration and hearing recovery. The mechanisms underlying the initiation of proliferation of postnatal cochlear progenitor cells and their transdifferentiation to HCs remain to be determined. We show that Notch inhibition initiates proliferation of supporting cells (SCs) and mitotic regeneration of HCs in neonatal mouse cochlea in vivo and in vitro. Through lineage tracing, we identify that a majority of the proliferating SCs and mitotic-generated HCs induced by Notch inhibition are derived from the Wnt-responsive leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5+) progenitor cells. We demonstrate that Notch inhibition removes the brakes on the canonical Wnt signaling and promotes Lgr5+ progenitor cells to mitotically generate new HCs. Our study reveals a new function of Notch signaling in limiting proliferation and regeneration potential of postnatal cochlear progenitor cells, and provides a new route to regenerate HCs from progenitor cells by interrupting the interaction between the Notch and Wnt pathways.
关键词：Notch1 ; β-catenin ; proliferation ; hair cells ; inner ear