Kappa opioid receptor contributes to EGF-stimulated neurite extension in development
Kappa opioid receptor contributes to EGF-stimulated neurite extension in development
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DOI：
10.1073/pnas.0912367107
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发表时间：
2010-01
期刊：
影响因子：
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通讯作者：
Nien‐Pei Tsai;Y. Tsui;J. Pintar;H. Loh;Li-Na Wei
中科院分区：
文献类型：
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作者：
Nien‐Pei Tsai;Y. Tsui;J. Pintar;H. Loh;Li-Na Wei
表皮生长因子（EGF）是一种有丝分裂原，也在发育过程中刺激神经突延伸，但其潜在机制尚不清楚。这项研究揭示了 kappa 阿片受体 (KOR) 在 EGF 刺激的神经突延伸中的功能作用及其潜在机制。在妊娠后期，胚胎脊髓中的 EGF 和活化的 EGF 受体 (EGFR) 水平升高，同时 KOR 和轴突延伸标记物、生长相关蛋白 43 (GAP43) 和瞬时轴突糖蛋白 1 (TAG-1) 的蛋白水平也升高。 KOR 缺失 (KOR−/−) 脊髓中的 GAP43 和 TAG-1 水平均显着降低，EGFR 抑制剂可有效降低野生型胚胎脊髓中的 KOR、GAP43 和 TAG-1 水平。对于 KOR−/− 或 KOR 敲低背根神经节 (DRG) 神经元，EGF 不再能有效刺激轴突延伸，这可以通过引入组成型 KOR 表达载体来挽救，但不能通过携带 5' 非翻译区的调节 KOR 载体来挽救，该非翻译区可以被生长因子受体结合蛋白 7 (Grb7) 结合和抑制。此外，通过应用抗强啡肽、KOR拮抗剂或EGFR抑制剂来阻断KOR激活可有效减少DRG神经元的轴突延伸。因此，发育过程中 EGF 刺激的轴突延伸至少部分是通过转录后水平 KOR 蛋白产量的特异性升高以及 KOR 信号传导的激活来介导的。结果还揭示了 EGF 在发育阶段增强某些 mRNA 转录后调节的作用。
Epidermal growth factor (EGF), a mitogen, also stimulates neurite extension during development, but the underlying mechanism is elusive. This study reveals a functional role for kappa opioid receptor (KOR) in EGF-stimulated neurite extension, and the underlying mechanism. EGF and activated EGF receptor (EGFR) levels are elevated in embryonic spinal cords during late gestation stages, with concurrent rise in protein levels of KOR and axon extension markers, growth-associated protein 43 (GAP43), and transient axonal glycoprotein-1 (TAG-1). Both GAP43 and TAG-1 levels are significantly lower in KOR-null (KOR−/−) spinal cords, and EGFR inhibitors effectively reduce the levels of KOR, GAP43, and TAG-1 in wild-type embryonic spinal cords. For KOR−/− or KOR-knockdown dorsal root ganglion (DRG) neurons, EGF can no longer effectively stimulate axon extension, which can be rescued by introducing a constitutive KOR expressing vector but not by a regulated KOR vector carrying its 5′ untranslated region, which can be bound and repressed by growth factor receptor-bound protein 7 (Grb7). Furthermore, blocking KOR activation by application of anti-dynorphin, KOR antagonist, or EGFR inhibitor effectively reduces axon extension of DRG neurons. Thus, EGF-stimulated axon extension during development is mediated, at least partially, by specific elevation of KOR protein production at posttranscriptional level, as well as activation of KOR signaling. The result also reveals an action of EGF to augment posttranscriptional regulation of certain mRNAs during developmental stages.