Daudet Nicolas, Ariza-McNaughton Linda, Lewis Julian
Vertebrate Development Laboratory, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Development. 2007 Jun;134(12):2369-78. doi: 10.1242/dev.001842.
Notch signalling is well-known to mediate lateral inhibition in inner ear sensory patches, so as to generate a balanced mixture of sensory hair cells and supporting cells. Recently, however, we have found that ectopic Notch activity at an early stage can induce the formation of ectopic sensory patches. This suggests that Notch activity may have two different functions in normal ear development, acting first to promote the formation of the prosensory patches, and then later to regulate hair-cell production within the patches. The Notch ligand Serrate1 (Jag1 in mouse and humans) is expressed in the patches from an early stage and may provide Notch activation during the prosensory phase. Here, we test whether Notch signalling is actually required for prosensory patch development. When we block Notch activation in the chick embryo using the gamma-secretase inhibitor DAPT, we see a complete loss of prosensory epithelial cells in the anterior otocyst, where they are diverted into a neuroblast fate via failure of Delta1-dependent lateral inhibition. The cells of the posterior prosensory patch remain epithelial, but expression of Sox2 and Bmp4 is drastically reduced. Expression of Serrate1 here is initially almost normal, but subsequently regresses. The patches of sensory hair cells that eventually develop are few and small. We suggest that, in normal development, factors other than Notch activity initiate Serrate1 expression. Serrate1, by activating Notch, then drives the expression of Sox2 and Bmp4, as well as expression of the Serrate1 gene itself. The positive feedback maintains Notch activation and thereby preserves and perhaps extends the prosensory state, leading eventually to the development of normal sensory patches.
众所周知，Notch信号通路在内耳感觉斑中介导侧向抑制，从而产生感觉毛细胞和支持细胞的平衡混合物。然而，最近我们发现早期异位的Notch活性可诱导异位感觉斑的形成。这表明Notch活性在正常耳发育中可能具有两种不同功能，首先促进前感觉斑的形成，然后调节斑内毛细胞的产生。Notch配体锯齿蛋白1（小鼠和人类中为Jag1）从早期就在斑中表达，并可能在前感觉阶段提供Notch激活。在这里，我们测试Notch信号通路是否实际上是前感觉斑发育所必需的。当我们使用γ-分泌酶抑制剂DAPT阻断鸡胚中的Notch激活时，我们看到前耳囊中前感觉上皮细胞完全缺失，这些细胞通过Delta1依赖性侧向抑制的失败而转变为神经母细胞命运。后前感觉斑的细胞保持上皮状态，但Sox2和Bmp4的表达大幅降低。这里锯齿蛋白1的表达最初几乎正常，但随后下降。最终发育的感觉毛细胞斑很少且很小。我们认为，在正常发育中，除Notch活性外的其他因素启动锯齿蛋白1的表达。锯齿蛋白1通过激活Notch，进而驱动Sox2和Bmp4的表达，以及锯齿蛋白1基因本身的表达。这种正反馈维持Notch激活，从而维持并可能扩展前感觉状态，最终导致正常感觉斑的发育。
