Overactivation of Notch1 signaling induces ectopic hair cells in the mouse inner ear in an age-dependent manner.
Overactivation of Notch1 signaling induces ectopic hair cells in the mouse inner ear in an age-dependent manner.
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DOI：
10.1371/journal.pone.0034123
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zuo J
中科院分区：
文献类型：
--
作者：
Liu Z;Owen T;Fang J;Zuo J
在小鼠内耳发育过程中，Notch 1信号首先指定感觉祖细胞，随后控制祖细胞进一步分化为毛细胞（HC）或支持细胞（SC）。在早期胚胎阶段，NICD（Notch 1胞内结构域）的过度激活导致异位HC形成。然而，目前还不清楚这种效果是否可以在胚胎后期或出生后阶段引起，这在小鼠HC再生的Notch 1信号的重新激活具有重要意义。我们进行了全面的体内诱导过度激活的NICD在不同的发展阶段。在CAGCreER+中; Rosa 26-NICDloxp/+小鼠在胚胎第10.5天（E10.5）接受他莫昔芬治疗时，在椭圆囊和耳蜗的非感觉区产生异位HC，而在E13给予他莫昔芬时，异位HC仅出现在椭圆囊中。在出生后第0天（P0）和P1天注射他莫昔芬时，在椭圆囊和耳蜗中均未观察到异位HC。有趣的是，Notch 1信号以非细胞自主的方式诱导新的HC，因为新的HC不表达NICD。与新HC相邻的是表达SC标志物Sox 10的细胞（NICD+或NICD阴性）。我们的数据表明，发育阶段决定了胚胎耳前体细胞和新生儿非感觉上皮细胞对NICD过度激活的反应性，并且野生型出生后内耳中的Notch 1信号传导不足以产生新的HC。因此，我们的遗传小鼠模型适合于测试可以与Notch 1途径协同相互作用以在出生后年龄产生HC的其他途径。
During mouse inner ear development, Notch1 signaling first specifies sensory progenitors, and subsequently controls progenitors to further differentiate into either hair cells (HCs) or supporting cells (SCs). Overactivation of NICD (Notch1 intracellular domain) at early embryonic stages leads to ectopic HC formation. However, it remains unclear whether such an effect can be elicited at later embryonic or postnatal stages, which has important implications in mouse HC regeneration by reactivation of Notch1 signaling. We performed comprehensive in vivo inducible overactivation of NICD at various developmental stages. In CAGCreER+; Rosa26-NICDloxp/+ mice, tamoxifen treatment at embryonic day 10.5 (E10.5) generated ectopic HCs in the non-sensory regions in both utricle and cochlea, whereas ectopic HCs only appeared in the utricle when tamoxifen was given at E13. When tamoxifen was injected at postnatal day 0 (P0) and P1, no ectopic HCs were observed in either utricle or cochlea. Interestingly, Notch1 signaling induced new HCs in a non-cell-autonomous manner, because the new HCs did not express NICD. Adjacent to the new HCs were cells expressing the SC marker Sox10 (either NICD+ or NICD-negative). Our data demonstrate that the developmental stage determines responsiveness of embryonic otic precursors and neonatal non-sensory epithelial cells to NICD overactivation, and that Notch 1 signaling in the wild type, postnatal inner ear is not sufficient for generating new HCs. Thus, our genetic mouse model is suitable to test additional pathways that could synergistically interact with Notch1 pathway to produce HCs at postnatal ages.
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影响因子：
3.7
作者：
Chen CM;Krohn J;Bhattacharya S;Davies B
通讯作者：
Davies B
影响因子：
64.8
作者：
Gubbels, Samuel P.;Woessner, David W.;Mitchell, John C.;Ricci, Anthony J.;Brigande, John V.
通讯作者：
Brigande, John V.
DOI：
10.1523/jneurosci.0312-08.2008
发表时间：
2008-07-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Driver EC;Pryor SP;Hill P;Turner J;Rüther U;Biesecker LG;Griffith AJ;Kelley MW
通讯作者：
Kelley MW
影响因子：
56.9
作者：
Bermingham, NA;Hassan, BA;Zoghbi, HY
通讯作者：
Zoghbi, HY
影响因子：
4.6
作者：
Brooker, R;Hozumi, K;Lewis, J
通讯作者：
Lewis, J