Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242-1078, USA.
Mol Cell Neurosci. 2011 Aug;47(4):306-15. doi: 10.1016/j.mcn.2011.05.010. Epub 2011 May 30.
Spiral ganglion Schwann cells (SGSCs) myelinate spiral ganglion neurons (SGNs) and represent a potential source of neurotrophic support for SGNs. Deafening due to loss of hair cells results in gradual degeneration and death of SGNs. Successful efforts to maintain or regenerate a functional auditory nerve may depend on a healthy population of SGSCs, yet the responses of SGSCs to neural injury remain largely unknown. Here we investigate the role of p75(NTR) in SGSC responses to gradual denervation. Following deafening, SGSCs in the osseous spiral lamina (OSL) and, subsequently, in Rosenthal's canal (RC) expressed elevated p75(NTR) compared to hearing controls. p75(NTR)-positive cells co-labeled with S100 and RIP antibodies (Schwann cell markers), but not with anti-neurofilament. The pattern of p75(NTR) expression mirrored the pattern of neural degeneration, beginning in the OSL of the cochlea base and later extending into the apex. SGSCs expressed sortilin, a p75(NTR) co-receptor for pro-neurotrophins. Both pro-nerve growth factor (pro-NGF) and pro-brain derived neurotrophic factor (proBDNF) induced apoptosis in cultured SGSCs. Deafened animals exhibited significantly higher levels of SGSC proliferation (as measured by BrdU uptake) compared to hearing animals while total Schwann cell density remained stable, suggesting a tight regulation of SGSC proliferation and cell death. SGSCs undergoing cell division lose p75(NTR) expression from the cell surface and demonstrate nuclear localization of the intracellular domain (ICD), raising the possibility that p75(NTR) cleavage and ICD nuclear localization regulate SGSC proliferation. These results suggest that p75(NTR) contributes to SGSC responses to deafening and neural degeneration.
螺旋神经节雪旺细胞（SGSCs）包绕螺旋神经节神经元（SGNs）并为其提供神经营养支持。毛细胞丧失导致的耳聋会引起 SGN 的逐渐退化和死亡。成功维持或再生功能性听神经可能依赖于健康的 SGSCs 群体，但 SGSCs 对神经损伤的反应在很大程度上仍不清楚。在这里，我们研究了 p75（NTR）在 SGSC 对逐渐去神经支配反应中的作用。耳聋后，骨螺旋板（OSL）中的 SGSCs 以及随后的 Rosenthal 管（RC）中的 SGSCs 表达的 p75（NTR）水平高于听力对照组。p75（NTR）阳性细胞与 S100 和 RIP 抗体（雪旺细胞标志物）共标记，但不与抗神经丝标记。p75（NTR）表达的模式与神经退化的模式相吻合，从耳蜗基底的 OSL 开始，然后延伸到耳蜗顶。SGSCs 表达了 sortilin，一种神经营养因子前体（pro-neurotrophin）的 p75（NTR）共受体。培养的 SGSCs 中，神经营养因子（nerve growth factor，NGF）和脑源性神经营养因子（brain derived neurotrophic factor，BDNF）都能诱导细胞凋亡。与听力动物相比，耳聋动物的 SGSC 增殖（通过 BrdU 摄取来衡量）明显更高，而总雪旺细胞密度保持稳定，这表明 SGSC 增殖和细胞死亡受到严格调控。进行有丝分裂的 SGSCs 会从细胞表面失去 p75（NTR）表达，并表现出细胞内结构域（ICD）的核定位，这提示 p75（NTR）裂解和 ICD 核定位可能调节 SGSC 增殖。这些结果表明，p75（NTR）参与了 SGSC 对耳聋和神经退化的反应。
