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信号通路被认为在哺乳动物内耳的发育中起着至关重要的作用。在科学研究补助金#18591866的支持<KAKENHI>下，我们使用特异性识别Notchl（actNl）的活化形式的抗体来研究Notchl的时空活化模式，以阐明Notch途径在内耳发育期间的多种作用。在胚胎第12.5天和第14.5天之间，actN 1主要在耳蜗上皮的内侧区域微弱地检测到，在那里也观察到Jagged 1（Jag 1）免疫反应性（IR）。Jag 1-IR在更清晰的区域中逐渐变强，最终定位于支持细胞中，而actN 1在重叠区域中被检测到。因此，假设在Jag 1和actN 1的表达之间存在正反馈回路。此外，actN 1在E14.5和E15.5之间开始在Mathl阳性毛细胞祖细胞周围的细胞中强烈表达。在围产期期间，在支持细胞系和大上皮嵴中都持续有强的actN 1-IR，但在P7结束，这表明Notchl激活可能最初在耳蜗上皮中划分前感觉区，然后通过经典的“侧向抑制”抑制祖细胞变成毛细胞。"

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."