Heregulin enhances regenerative proliferation in postnatal rat utricular sensory epithelium after ototoxic damage

作     者：Zheng, JL Frantz, G Lewis, AK Sliwkowski, M Gao, WQ 

作者机构：Genentech Inc Dept Neurosci San Francisco CA 94080 USA Genentech Inc Dept Pathol San Francisco CA 94080 USA Genentech Inc Dept Mol Oncol San Francisco CA 94080 USA 

出 版 物：《JOURNAL OF NEUROCYTOLOGY》 (脑细胞生物学杂志)

年 卷 期：1999年第28卷第10-11期

页      面：901-912页

核心收录：

学科分类：0710[理学-生物学] 1001[医学-基础医学(可授医学、理学学位)] 07[理学] 071003[理学-生理学] 

主　　题：细胞计数/药物作用 细胞分裂/药物作用 细胞 培养的 剂量效应关系 药物 内耳/代谢 上皮细胞/细胞学 上皮细胞/药物作用 上皮细胞/代谢 基因表达/药物作用 庆大霉素类/药理学 毛细胞 听觉/细胞学 毛细胞 听觉/药物作用 迷路支持细胞/细胞学 迷路支持细胞/药物作用 配体 有丝分裂原/代谢 有丝分裂原/毒性 神经调节蛋白1/遗传学 神经调节蛋白1/代谢 神经调节蛋白1/药理学 RNA 信使/生物合成 大鼠 Wistar 受体 表皮生长因子/遗传学 受体 表皮生长因子/代谢 受体 erbB-2/遗传学 受体 erbB-2/代谢 受体 erbB-3/遗传学 受体 erbB-3/代谢 再生/药物作用 再生/生理学 球囊和椭圆囊/细胞学 球囊和椭圆囊/药物作用 球囊和椭圆囊/代谢 胸苷/代谢 增量调节/药物作用 动物 大鼠 

摘      要：Hair cell loss due to acoustic and ototoxic damage often leads to hearing and balance impairments. Although a spontaneous event in chicks and lower vertebrates, hair cell replacement occurs at a much lower frequency in mammals presumably due to a very low rate of supporting cell proliferation following injury. We report here that heregulin, a member of the neuregulin family, dramatically enhances proliferation of supporting cells in postnatal rat utricular epithelial sheet cultures after gentamicin treatment, as revealed by bromo-deoxyuridine (BrdU) immunocytochemistry. A dose-dependent study shows that the maximal effects of heregulin are achieved at 3 nM. The mitogenic effects of heregulin are confirmed in utricular whole mount cultures. Autoradiography of the utricular whole mount cultures shows that heregulin also enhances the number of tritiated thymidine-labeled cells within the hair cell layer. TaqMan quantitative RT-PCR analysis and immunocytochemistry reveal that heregulin and its binding receptors (ErbB-2, ErbB-3 and ErbB-4) are expressed in the inner ear sensory epithelium. Of several ligands activating various ErbB receptors, including heregulin, neuregulin-3, beta-cellulin, heparin binding-epidermal growth factor (HB-EGF), transforming growth factor-alpha (TGF-alpha) and EGF, heregulin shows the most potent mitogenic effects on supporting cells. Because neuregulin-3 that signals only through ErbB-4 does not show an effect, these data suggest that activation of the ErbB-2-ErbB-3 heterodimeric complexes, rather than ErbB-4, is critical for the proliferative response in the utricular sensory epithelium. In addition, gentamicin treatment induces an upregulation of heregulin mRNA. Considered together, heregulin may play an important role in hair cell regeneration following ototoxic damage.