The investigation of the roles of Notch signaling pathway during the mammalian inner ear development and its application to the to the hair cell regeneration

Notch信号通路在哺乳动物内耳发育过程中起着至关重要的作用。在科学研究助学金(Grant-in-aid for Science Research&lt；KAKENHI&GT；#18591866)的支持下，我们使用特异性识别Notch1(ActN1)激活形式的抗体来研究Notch1的时空激活模式，以阐明Notch途径在内耳发育中的多重作用。从胚胎12.5天到胚胎14.5天，ActN1主要分布在耳蜗腺上皮的内侧，Jagged1(Jag1)免疫反应(IR)也在那里观察到。Jag1-IR在更清晰的区域逐渐增强，最终定位于支持细胞，而actN1在重叠区域检测到，因此假设Jag1和actN1的表达之间存在正反馈环。此外，在E14.5和E15.5之间，在Mathl阳性毛细胞祖细胞周围的细胞中，actN1开始强烈表达。在围产期，支持细胞线和大上皮脊中持续着强大的actN1-IR，但到P7结束，这表明Notch1的激活可能最初划定了耳蜗上皮中的前感觉区，然后通过经典的“侧向抑制”抑制前体细胞成为毛细胞。

The Notch signaling pathway has been thought to play a crucial role in the development of mammalian inner ear. Supported by the Grant-in-Aid for Scientific Research <KAKENHI> #18591866, we investigated the spatio-temporal activation pattern of Notchl using the antibody that specifically recognizes the activated form of Notchl (actN1) to clarify the multiple roles of the Notch pathway during the inner ear development. Between embryonic days (E) 12.5 and E14.5, actN1 was weakly detected mainly in the medial region of the cochlear epithelium, where Jagged1 (Jag1)-immunoreactivity (IR) was also observed. Jag1-IR gradually became stronger in a more sharply defined area, finally becoming localized in supporting cells, while actN1 was detected in an overlapping area Thus, a positive feed-back loop was assumed to exit between the expression of Jag1 and actN1. In addition, actN1 started to be strongly expressed in the cells surrounding Mathl-positive hair cell progenitors between E14.5 and E15.5. Strong actN1-IR continued in both a supporting cell linege and in the greater epithelial ridge during the perinatal stage but ended by P7, suggesting that Notchl activation may initially demarcate a prosensory region in the cochlear epithelium and then inhibit progenitor cells from becoming hair cells via classical "lateral inhibition."