Math1 Gene Transfer Generates New Cochlear Hair Cells in Mature Guinea Pigs In Vivo
Math1 Gene Transfer Generates New Cochlear Hair Cells in Mature Guinea Pigs In Vivo
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DOI：
10.1523/jneurosci.23-11-04395.2003
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发表时间：
2003-06
期刊：
影响因子：
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通讯作者：
K. Kawamoto;S. Ishimoto;R. Minoda;D. Brough;Y. Raphael
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文献类型：
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作者：
K. Kawamoto;S. Ishimoto;R. Minoda;D. Brough;Y. Raphael
哺乳动物耳蜗中的毛细胞损失是不可逆的，并导致永久性听力损失。Math 1是果蝇无调基因的基本螺旋-环-螺旋转录因子同源物，是耳蜗发育过程中毛细胞分化的正调控因子。发育中的毛细胞表达Math 1，而非感觉细胞不表达。我们着手确定在耳蜗非感觉细胞中Math 1过表达对这些细胞表型的影响。我们证明，在体内接种的腺病毒与Math 1基因插入到成熟的豚鼠耳蜗内淋巴导致Math 1过表达的非感觉耳蜗细胞，从Math 1蛋白的存在下，在支持细胞的Corti器官和相邻的非感觉上皮细胞。Math 1过表达导致Corti器官中未成熟毛细胞的出现，以及齿间细胞、内沟和Hensen细胞区域中Corti器官附近的新毛细胞的出现。轴突从听神经束延伸到一些新的毛细胞，这表明新的细胞吸引听觉神经元。我们的结论是，在成熟的耳蜗中的非感觉细胞保留的能力，以产生新的毛细胞后，在体内过表达的数学1和数学1是必要的，足以直接在这些成熟的非感觉细胞的毛细胞分化。
Hair cell loss in the mammalian cochlea is irreversible and results in permanent hearing loss. Math1, the basic helix-loop-helix transcription factor homolog of the Drosophila atonal gene, is a positive regulator of hair cell differentiation during cochlear development. Developing hair cells express Math1, and nonsensory cells do not. We set out to determine the outcome of overexpression of Math1 in nonsensory cells of the cochlea on the phenotype of these cells. We demonstrate that in vivo inoculation of adenovirus with the Math1 gene insert into the endolymph of the mature guinea pig cochlea results in Math1 overexpression in nonsensory cochlear cells, as evident from the presence of Math1 protein in supporting cells of the organ of Corti and in adjacent nonsensory epithelial cells. Math1 overexpression leads to the appearance of immature hair cells in the organ of Corti and new hair cells adjacent to the organ of Corti in the interdental cell, inner sulcus, and Hensen cell regions. Axons are extended from the bundle of auditory nerve toward some of the new hair cells, suggesting that the new cells attract auditory neurons. We conclude that nonsensory cells in the mature cochlea retain the competence to generate new hair cells after overexpression of Math1 in vivo and that Math1 is necessary and sufficient to direct hair cell differentiation in these mature nonsensory cells.