Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer.
Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer.
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DOI：
10.1038/nature07265
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发表时间：
2008-09-25
期刊：
影响因子：
64.8
通讯作者：
Brigande, John V.
中科院分区：
文献类型：
--
作者：
Gubbels, Samuel P.;Woessner, David W.;Mitchell, John C.;Ricci, Anthony J.;Brigande, John V.
哺乳动物耳蜗中的感觉毛细胞将机械刺激转化为有助于听觉的电脉冲。毛细胞及其支配神经元的损失是听力障碍的最常见原因。无调同源物1（Atoh 1，也称为Math 1）是毛细胞发育所需的基本螺旋-环-螺旋转录因子，其在体外和体内的错误表达产生毛细胞样细胞。已经提出了基于Atoh 1的基因治疗来改善听觉和前庭功能障碍。然而，Atoh 1错误表达诱导的假定毛细胞的生物物理特性尚未得到表征。在这里，我们表明，在子宫内基因转移Atoh 1产生功能性的额外的毛细胞在小鼠耳蜗。诱导的毛细胞显示静纤毛束，吸引神经元突起，并表达带状突触标记物C-末端结合蛋白2（Ctbp 2）。此外，毛细胞能够进行机械电转导，并显示与年龄相适应的特化基底侧电导。我们的研究结果表明，操纵细胞命运的转录因子的错误表达产生功能的感觉细胞在出生后的哺乳动物耳蜗。我们预计，我们的子宫内基因转移模式将使基因治疗的设计和验证，以改善人类耳聋小鼠模型的听力损失。
Sensory hair cells in the mammalian cochlea convert mechanical stimuli into electrical impulses that subserve audition. Loss of hair cells and their innervating neurons is the most frequent cause of hearing impairment. Atonal homolog 1 (Atoh1, also known as Math1) is a basic helix-loop-helix transcription factor required for hair cell development and its misexpression in vitro and in vivo generates hair-cell-like cells. Atoh1-based gene therapy to ameliorate auditory and vestibular dysfunction has been proposed. However, the biophysical properties of putative hair cells induced by Atoh1 misexpression have not been characterized. Here we show that in utero gene transfer of Atoh1 produces functional supernumerary hair cells in the mouse cochlea. The induced hair cells display stereociliary bundles, attract neuronal processes, and express the ribbon synapse marker C-terminal binding protein 2 (Ctbp2). Moreover, the hair cells are capable of mechanoelectrical transduction and display basolateral conductances with age-appropriate specializations. Our results demonstrate that manipulation of cell fate by transcription factor misexpression produces functional sensory cells in the postnatal mammalian cochlea. We anticipate that our in utero gene transfer paradigm will enable the design and validation of gene therapies to ameliorate hearing loss in mouse models of human deafness.
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DOI：
10.1083/jcb.137.6.1287
发表时间：
1997-06-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hasson T;Gillespie PG;Garcia JA;MacDonald RB;Zhao Y;Yee AG;Mooseker MS;Corey DP
通讯作者：
Corey DP
影响因子：
25
作者：
Zheng, JL;Gao, WQ
通讯作者：
Gao, WQ
影响因子：
5.3
作者：
Waguespack, Jessica;Salles, Felipe T.;Ricci, Anthony J.
通讯作者：
Ricci, Anthony J.
DOI：
10.1073/pnas.92.21.9815
发表时间：
1995-10-10
影响因子：
11.1
作者：
HASSON, T;HEINTZELMAN, MB;MOOSEKER, MS
通讯作者：
MOOSEKER, MS
影响因子：
5.3
作者：
Jones, JM;Montcouquiol, M;Kelley, MW
通讯作者：
Kelley, MW