Sox2 signaling in prosensory domain specification and subsequent hair cell differentiation in the developing cochlea
Sox2 signaling in prosensory domain specification and subsequent hair cell differentiation in the developing cochlea
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DOI：
10.1073/pnas.0808175105
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发表时间：
2008-11-25
影响因子：
11.1
通讯作者：
Kelley, Matthew W.
中科院分区：
文献类型：
--
作者：
Dabdoub, Alain;Puligilla, Chandrakala;Kelley, Matthew W.
Sox 2是一种高迁移率的转录因子，是发育中的内耳前感觉域的最早标志物之一。在人类中，SOX 2的突变导致感觉神经性听力损失，在小鼠中进行的功能丧失研究表明，SOX 2是耳蜗中前感觉形成所必需的。然而，Sox 2的具体作用尚未确定。在这里，我们说明了一个动态的作用，Sox 2作为一个早期的允许因素，在prosensory域的形成，随后与Atoh1，毛细胞发育所必需的bHLH蛋白的相互拮抗关系。我们证明，Sox2水平降低导致早熟毛细胞分化和内毛细胞的过度生产，这些影响可能是通过Sox2和bHLH分子Atoh1之间的拮抗相互作用介导的。使用功能获得和丧失实验，我们为负责耳蜗前感觉域形成的分子途径提供了证据。Sox 2的表达由Notch信号传导促进，同源框转录因子Prox 1是Sox 2的下游靶点。这些结果表明，Sox 2在耳蜗内感觉细胞的发育，规范和维护中起着重要而多样的作用。
Sox2 is a high-mobility transcription factor that is one of the earliest markers of developing inner ear prosensory domains. In humans, mutations in SOX2 cause sensorineural hearing loss and a loss of function study in mice showed that Sox2 is required for prosensory formation in the cochlea. However, the specific roles of Sox2 have not been determined. Here we illustrate a dynamic role of Sox2 as an early permissive factor in prosensory domain formation followed by a mutually antagonistic relationship with Atoh1, a bHLH protein necessary for hair cell development. We demonstrate that decreased levels of Sox2 result in precocious hair cell differentiation and an over production of inner hair cells and that these effects are likely mediated through an antagonistic interaction between Sox2 and the bHLH molecule Atoh1. Using gain- and loss-of-function experiments we provide evidence for the molecular pathway responsible for the formation of the cochlear prosensory domain. Sox2 expression is promoted by Notch signaling and Prox1, a homeobox transcription factor, is a downstream target of Sox2. These results demonstrate crucial and diverse roles for Sox2 in the development, specification, and maintenance of sensory cells within the cochlea.