The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear
The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear
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DOI：
10.1242/dev.02002
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发表时间：
2005-10-01
期刊：
影响因子：
4.6
通讯作者：
Gridley, T
中科院分区：
文献类型：
--
作者：
Kiernan, AE;Cordes, R;Gridley, T
哺乳动物的听觉感觉上皮（Corti器官）包含感觉毛细胞和非感觉支持细胞，它们排列成高度模式化的马赛克。Notch介导的侧抑制是产生这种感觉马赛克的机制。先前的研究表明，缺乏Notch配体JAG 2的小鼠在耳蜗中分化出额外的毛细胞，这与侧抑制模型一致。然而，尚不清楚为什么在Jag 2突变小鼠中只观察到毛细胞产量相对适度的增加。在这里，我们发现另一个Notch配体DLL 1与JAG 2在调节耳蜗毛细胞分化中协同作用。我们还表明，通过条件失活，这些配体可能通过NOTCH 1受体的信号。Dll 1/Jag 2双突变体中的额外毛细胞主要通过细胞命运的转换而产生，而不是通过过度增殖。虽然这些结果证明了Notch介导的侧抑制在耳蜗毛细胞图案化过程中的重要作用，但我们也检测到异常延长的细胞增殖，其优先影响Corti器官中的支持细胞。我们的研究结果表明，Notch通路在调节耳蜗细胞分化和模式中起着双重作用，通过侧抑制和细胞增殖的控制起作用。
The mammalian auditory sensory epithelium, the organ of Corti, contains sensory hair cells and nonsensory supporting cells arranged in a highly patterned mosaic. Notch-mediated lateral inhibition is the proposed mechanism for creating this sensory mosaic. Previous work has shown that mice lacking the Notch ligand JAG2 differentiate supernumerary hair cells in the cochlea, consistent with the lateral inhibitory model. However, it was not clear why only relatively modest increases in hair cell production were observed in Jag2 mutant mice. Here, we show that another Notch ligand, DLL1, functions synergistically with JAG2 in regulating hair cell differentiation in the cochlea. We also show by conditional inactivation that these ligands probably signal through the NOTCH1 receptor. Supernumerary hair cells in Dll1/Jag2 double mutants arise primarily through a switch in cell fate, rather than through excess proliferation. Although these results demonstrate an important role for Notch-mediated lateral inhibition during cochlear hair cell patterning, we also detected abnormally prolonged cellular proliferation that preferentially affected supporting cells in the organ of Corti. Our results demonstrate that the Notch pathway plays a dual role in regulating cellular differentiation and patterning in the cochlea, acting both through lateral inhibition and the control of cellular proliferation.