Nishimura K, Weichert R M, Liu W, Davis R L, Dabdoub A
Biological Sciences, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
Department of Surgery/Otolaryngology, UCSD School of Medicine, La Jolla, CA 92093, USA.
Neuroscience. 2014 Sep 5;275:125-35. doi: 10.1016/j.neuroscience.2014.05.067. Epub 2014 Jun 11.
Primary auditory neurons (ANs) in the mammalian cochlea play a critical role in hearing as they transmit auditory information in the form of electrical signals from mechanosensory cochlear hair cells in the inner ear to the brainstem. Their progressive degeneration is associated with disease conditions, excessive noise exposure and aging. Replacement of ANs, which lack the ability to regenerate spontaneously, would have a significant impact on research and advancement in cochlear implants in addition to the amelioration of hearing impairment. The aim of this study was to induce a neuronal phenotype in endogenous non-neural cells in the cochlea, which is the essential organ of hearing. Overexpression of a neurogenic basic helix-loop-helix transcription factor, Ascl1, in the cochlear non-sensory epithelial cells induced neurons at high efficiency at embryonic, postnatal and juvenile stages. Moreover, induced neurons showed typical properties of neuron morphology, gene expression and electrophysiology. Our data indicate that Ascl1 alone or Ascl1 and NeuroD1 is sufficient to reprogram cochlear non-sensory epithelial cells into functional neurons. Generation of neurons from non-neural cells in the cochlea is an important step for the regeneration of ANs in the mature mammalian cochlea.
哺乳动物耳蜗中的初级听觉神经元（ANs）在听力中起着关键作用，因为它们以电信号的形式将听觉信息从内耳的机械感觉性耳蜗毛细胞传递到脑干。它们的渐进性退化与疾病状况、过度噪音暴露和衰老有关。由于ANs缺乏自发再生能力，因此其替代不仅会对改善听力障碍产生重大影响，还会对人工耳蜗的研究和进展产生重大影响。本研究的目的是在耳蜗（听力的重要器官）的内源性非神经细胞中诱导出神经元表型。在耳蜗非感觉上皮细胞中过表达神经源性碱性螺旋-环-螺旋转录因子Ascl1，在胚胎期、出生后和幼年阶段均能高效诱导神经元产生。此外，诱导神经元表现出典型的神经元形态、基因表达和电生理特性。我们的数据表明，单独的Ascl1或Ascl1与NeuroD1足以将耳蜗非感觉上皮细胞重编程为功能性神经元。从耳蜗中的非神经细胞生成神经元是成熟哺乳动物耳蜗中ANs再生的重要一步。
