Notch signaling is required for the generation of hair cells and supporting cells in the mammalian inner ear
Notch signaling is required for the generation of hair cells and supporting cells in the mammalian inner ear
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DOI：
10.1073/pnas.1003089107
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发表时间：
2010-09-07
影响因子：
11.1
通讯作者：
Kiernan, Amy E.
中科院分区：
文献类型：
--
作者：
Pan, Wei;Jin, Ying;Kiernan, Amy E.
感音神经性耳聋和平衡障碍是人类常见的疾病，常由内耳毛细胞和支持细胞组成的感觉上皮缺陷引起。谱系研究表明，毛细胞和支持细胞来自共同的祖细胞，但这些祖细胞是如何产生的仍不清楚。尽管有多种分子参与了感觉前体细胞的发育，但在哺乳动物内耳中，没有一种分子被证明是这些感觉前体细胞所必需的。在这里，使用功能丧失和功能获得两种方法，我们证明Jagged1(JAG1)介导的Notch信号对于感觉前体细胞的产生既是必需的，也是充分的。具体地说，我们发现JAG1信号的丢失导致了较小的感觉前体区域，而不会对细胞增殖或细胞死亡产生初始影响，这表明JAG1参与了初始指定事件。为了进一步测试Notch信号是否参与了感觉前体细胞的指定，我们使用Tet-on/Cre联合诱导系统在小鼠中瞬时表达了Notch1受体(NICD)的激活形式。NiCd的表达导致耳蜗区和前庭无感觉区的异位毛细胞和支持细胞。这些数据表明，Notch在内耳中指定了感觉前体细胞，并且Notch的诱导对于哺乳动物内耳中毛细胞和支持细胞的再生或替换可能是重要的。
Sensorineural deafness and balance dysfunction are common impairments in humans frequently caused by defects in the sensory epithelium of the inner ear, composed of hair cells and supporting cells. Lineage studies have shown that hair cells and supporting cells arise from a common progenitor, but how these progenitors are generated remains unknown. Although various molecules have been implicated in the development of the sensory progenitors, none has been shown to be required for the specification of these progenitors in the mammalian inner ear. Here, using both loss-of-function and gain-of-function approaches, we show that Jagged1 (JAG1)-mediated Notch signaling is both required and sufficient for the generation of the sensory progenitors. Specifically, we find that loss of JAG1 signaling leads to smaller sensory progenitor regions without initial effects on proliferation or cell death, indicating that JAG1 is involved in initial specification events. To further test whether Notch signaling is involved in specification of the sensory progenitors, we transiently expressed an activated form of the Notch1 receptor (NICD) using a combined Tet-On/Cre induction system in the mouse. NICD expression resulted in ectopic hair cells and supporting cells in the nonsensory regions of the cochlea and vestibule. These data indicate that Notch specifies sensory progenitors in the inner ear, and that induction of Notch may be important for regenerating or replacing hair cells and supporting cells in the mammalian inner ear.