Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
Dev Cell. 2012 Feb 14;22(2):377-90. doi: 10.1016/j.devcel.2011.12.006.
Inner-ear hair cell differentiation requires Atoh1 function, while Eya1, Six1, and Sox2 are coexpressed in sensory progenitors and mutations in these genes cause sensorineural hearing loss. However, how these genes are linked functionally and the transcriptional networks controlling hair cell induction remain unclear. Here, we show (1) that Eya1/Six1 are necessary for hair cell development, and their coexpression in mouse cochlear explants is sufficient to induce hair cell fate in the nonsensory epithelium expressing low-level Sox2 by activating not only Atoh1-dependent but also Atoh1-independent pathways and (2) that both pathways induce Pou4f3 to promote hair cell differentiation. Sox2 cooperates with Eya1/Six1 to synergistically activate Atoh1 transcription via direct binding to the conserved Sox- and Six-binding sites in Atoh1 enhancers, and these proteins physically interact. Our findings demonstrate that direct and cooperative interactions between the Sox2, Six1, and Eya1 proteins coordinate Atoh1 expression to specify hair cell fate.
内耳毛细胞的分化需要 Atoh1 功能，而 Eya1、Six1 和 Sox2 在感觉祖细胞中共同表达，这些基因的突变会导致感觉神经性听力损失。然而，这些基因如何在功能上联系在一起，以及控制毛细胞诱导的转录网络仍然不清楚。在这里，我们表明：（1）Eya1/Six1 对于毛细胞的发育是必要的，它们在小鼠耳蜗外植体中的共表达足以通过激活不仅依赖于 Atoh1 而且独立于 Atoh1 的途径，在表达低水平 Sox2 的非感觉上皮中诱导毛细胞命运；（2）这两种途径都诱导 Pou4f3 来促进毛细胞的分化。Sox2 与 Eya1/Six1 合作，通过直接结合 Atoh1 增强子中的保守 Sox 和 Six 结合位点，协同激活 Atoh1 转录，并且这些蛋白质相互作用。我们的研究结果表明，Sox2、Six1 和 Eya1 蛋白之间的直接和合作相互作用协调 Atoh1 的表达以指定毛细胞命运。
