Hedgehog signaling regulates sensory cell formation and auditory function in mice and humans.
Hedgehog signaling regulates sensory cell formation and auditory function in mice and humans.
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DOI：
10.1523/jneurosci.0312-08.2008
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发表时间：
2008-07-16
期刊：
影响因子：
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通讯作者：
Kelley MW
中科院分区：
文献类型：
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作者：
Driver EC;Pryor SP;Hill P;Turner J;Rüther U;Biesecker LG;Griffith AJ;Kelley MW
听觉是通过位于内耳特殊感觉上皮内的有限数量的机械感觉毛细胞介导的。适当数量的毛细胞的形成和这些细胞的位置对正常的听觉功能至关重要。然而，调控这种上皮形成的因素仍然知之甚少。转录因子GLI3 （Hedgehog （HH）通路的下游效应因子）的截断突变可导致HH信号的部分缺失并导致Pallister-Hall综合征（PHS）。在这里，我们报告了来自小灵通小鼠模型（Gli3Δ699）的耳蜗，它只产生Gli3的截断抑制形式，具有可变的渗透表型，包括感觉上皮大小的增加和Kölliker器官（KO）中大异位感觉斑块的发展。与小鼠模型一致，一些小灵通个体在广泛的频率范围内表现出听力损失。此外，体外HH信号的抑制导致前感觉结构域的大小增加，前感觉结构域是产生感觉上皮的前体群体，而Sonic Hedgehog （Shh）治疗可抑制前感觉的形成。最后，我们证明了耳蜗内的HH信号调节前感觉标志物的表达，并且HH在KO中的作用依赖于Notch的激活，Notch是前感觉命运的诱导剂。这些结果表明HH信号在耳蜗内毛细胞的前感觉结构域的规格、大小和位置中起着关键作用。
Auditory perception is mediated through a finite number of mechanosensory hair cells located in a specialized sensory epithelium within the inner ear. The formation of the appropriate number of hair cells and the location of those cells is crucial for normal auditory function. However, the factors that regulate the formation of this epithelium remain poorly understood. Truncating mutations in the transcription factor GLI3, a downstream effector of the Hedgehog (HH) pathway, lead to a partial loss of HH signaling and cause Pallister-Hall syndrome (PHS). Here we report that cochleae from a mouse model of PHS (Gli3Δ699), which produces only the truncated, repressor form of Gli3, have a variably penetrant phenotype that includes an increase in the size of the sensory epithelium and the development of large ectopic sensory patches in Kölliker’s Organ (KO). Consistent with the mouse model, some PHS individuals exhibit hearing loss across a broad range of frequencies. Moreover, inhibition of HH signaling in vitro results in an increase in the size of the prosensory domain, a precursor population that gives rise to the sensory epithelium, while treatment with Sonic Hedgehog (Shh) inhibits prosensory formation. Finally, we demonstrate that HH signaling within the cochlea regulates expression of prosensory markers and that the effects of HH in KO are dependent on activation of Notch, an inducer of prosensory fate. These results suggest that HH signaling plays a key role in the specification, size, and location of the prosensory domain, and therefore of hair cells, within the cochlea.