Inactivation of fibroblast growth factor receptor signaling in myelinating glial cells results in significant loss of adult spiral ganglion neurons accompanied by age-related hearing impairment.
Inactivation of fibroblast growth factor receptor signaling in myelinating glial cells results in significant loss of adult spiral ganglion neurons accompanied by age-related hearing impairment.
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DOI：
10.1002/jnr.22164
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发表时间：
2009-11-15
影响因子：
4.2
通讯作者：
Bansal, R.
中科院分区：
文献类型：
--
作者：
Wang, S. J.;Furusho, M.;D'Sa, C.;Kuwada, S.;Conti, L.;Morest, D. K.;Bansal, R.
听力损失可归因于许多因素，包括听觉通路中感觉神经元的变性和耳蜗神经沿着的脱髓鞘。成纤维细胞生长因子（FGF）通过四种受体（Fgfrs）发出信号，由听觉神经元产生，在耳蜗的胚胎发育和声音诱导损伤的神经保护中起关键作用。然而，FGF信号转导在维持成年和衰老小鼠正常听觉功能中的作用仍有待阐明。此外，神经胶质细胞的贡献，耳蜗神经髓鞘，知之甚少。为了解决这些问题，我们产生了转基因小鼠，其中Fgfr 1和Fgfr 2在雪旺细胞和少突胶质细胞中特异性失活，但在神经元中不失活。成年突变小鼠表现出迟发性听力障碍，随着年龄的增长而明显进展。听力障碍伴随着有髓螺旋神经节神经元的显著损失。病变延伸到耳蜗核，没有明显的髓鞘或缺失的神经胶质细胞本身的损失。这表明FGF受体介导的神经胶质功能的扰动导致神经元的神经胶质支持的衰减，导致其听觉功能的丧失和损害。因此，FGF/FGF受体信号提供了一种潜在的新机制，维持神经元和神经胶质细胞之间的相互作用，在成年和老龄动物。因此，神经胶质细胞和FGF受体信号传导功能障碍可能与正常衰老相关的神经退行性听力损失有关。
Hearing loss has been attributed to many factors, including degeneration of sensory neurons in the auditory pathway and demyelination along the cochlear nerve. Fibroblast growth factors (FGFs), which signal through four receptors (Fgfrs), are produced by auditory neurons and play a key role in embryonic development of the cochlea and in neuroprotection against sound-induced injury. However, the role of FGF signaling in the maintenance of normal auditory function in adult and aging mice remains to be elucidated. Furthermore, the contribution of glial cells, which myelinate the cochlear nerves, is poorly understood. To address these questions, we generated transgenic mice in which Fgfr1 and Fgfr2 were specifically inactivated in Schwann cells and oligodendrocytes but not in neurons. Adult mutant mice exhibited late onset of hearing impairment, which progressed markedly with age. The hearing impairment was accompanied by significant loss of myelinated spiral ganglion neurons. The pathology extended into the cochlear nucleus, without apparent loss of myelin or of the deletion-bearing glial cells themselves. This suggests that perturbation of FGF receptor-mediated glial function leads to the attenuation of glial support of neurons, leading to their loss and impairment of auditory functions. Thus, FGF/FGF receptor signaling provides a potentially novel mechanism of maintaining reciprocal interactions between neurons and glia in adult and aging animals. Dysfunction of glial cells and FGF receptor signaling may therefore be implicated in neurodegenerative hearing loss associated with normal aging.
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影响因子：
1.9
作者：
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通讯作者：
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影响因子：
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作者：
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