Role of Neuronal differentiation and Regeneration of VHL Tumor Suppressor Gene

VHL抑癌基因神经元分化和再生的作用

• 批准号: 12671374
• 负责人: KANNO Hiroshi
• 金额: $ 1.15万
• 依托单位: Yokohama City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671374/
• 关键词: VHL gene; Neuronal differentiation; Neuronal regeneration; 神経分化; 神経再生; 神経芽細胞腫; パーキンソン病

VHL gene and protein are expressed in neuronal cells of fetus and adult brain. However, the role of VHL gene in central nervous system (CNS) has not been elucidated. VHL gene might modify the various gene expressions of during embryogenesis and tumorigenesis in CNS. We investigated the role of VHL gene in CNS development using rodent CNS progenitor cells. Here we show that expression of the VHL protein is correlated with neuronal differentiation but not with glial differentiation in central nervous system progenitor cells, and also show that VHL gene transduction induces neuronal differentiation. In addition, a VHLmRNA antisense oligonucleotide inhibits differentiation of CNS progenitor cells and up-regulates their cell cycle. VHL protein can change NSCs into mature functional neuron in the electrophysiological function in vitro and also can differentiate dopamine-secreting neurons in brains of Parkinson model rats. VHL protein plays a critical role for neuronal differentiation of human neuroblastoma cells. Neuroblastoma cells stably expressing VHL protein had neurite-like processes with varicosities, distinct expression of the neuronal markers neuropeptide Y and neurofilament 200, acquired regulated neurosecretion competence in response to depolarizing and cholinergic stimuli, and had large voltage-gated fast sodium currents and delayed rectifier potassium (Kv) currents compatible with mature neurons. In conclusion, VHL gene plays an essential role in neuronal differentiation and VHL-gene induction cells are useful for neuronal regeneration as powerful tool

VHL基因和蛋白在胎儿和成人脑神经元细胞中均有表达。然而，VHL基因在中枢神经系统（CNS）中的作用尚未阐明。VHL基因可能改变中枢神经系统胚胎发生和肿瘤发生过程中各种基因的表达。我们利用啮齿动物中枢神经系统祖细胞研究了VHL基因在中枢神经系统发育中的作用。本研究表明，VHL蛋白的表达与中枢神经系统祖细胞的神经元分化相关，而与胶质分化无关，并且VHL基因的转导诱导了神经元分化。此外，VHLmRNA反义寡核苷酸抑制中枢神经系统祖细胞的分化并上调其细胞周期。VHL蛋白能使NSCs在体外电生理功能上转变为成熟的功能神经元，也能分化帕金森模型大鼠脑内分泌多巴胺的神经元。VHL蛋白在人神经母细胞瘤细胞的神经分化中起关键作用。稳定表达VHL蛋白的神经母细胞瘤细胞具有曲张的神经突样突起，神经元标记物神经肽Y和神经丝200表达明显，在去极化和胆碱能刺激下获得受调节的神经分泌能力，具有与成熟神经元兼容的大电压门控快速钠电流和延迟整钾（Kv）电流。综上所述，VHL基因在神经元分化中起着重要的作用，VHL基因诱导细胞是神经元再生的有力工具

项目成果

菅野洋: "血管芽腫"別冊日本臨床領域症候群シリーズ神経症候群III. 28. 169-172 (2000)

Hiroshi Kanno：“血管母细胞瘤”特别版日本临床区综合症系列神经综合症 III 28. 169-172 (2000)

Kannno H, SaijooqueF, U H.S, et al.: "Role of the von Hippel-Lindau tumor suppressor protein during neuronal differentiation"Cancer Research. 60. 2820-2824 (2000)

Kannno H、SaijooqueF、U H.S 等人：“von Hippel-Lindau 肿瘤抑制蛋白在神经元分化过程中的作用”癌症研究。

Yoshida M,Ashida K,Kanno H, et al.: "Germline mutation analysis in patients with von Hippel-Lindau disease in Japan"Japanese Journal of Cancer Research. 91. 204-212 (2000)

Yoshida M、Ashida K、Kanno H 等人：“日本 von Hippel-Lindau 病患者的种系突变分析”日本癌症研究杂志。

Sato H, Hattori S, Kawamoto S, Kudoh I, Hayashi A, Yamamoto I, Yoshinari M, Minami M, Kanno H: "ln vivo gene gun-mediated DNA delivery into rodent brain tissue"Biochem Biophys Res Comun. 270(1). 163-170 (2000)

Sato H、Hattori S、Kawamoto S、Kudoh I、Hayashi A、Yamamoto I、Yoshinari M、Minami M、Kanno H：“体内基因枪介导的 DNA 递送至啮齿动物脑组织”Biochem Biophys Res Comun。

菅野洋: "血管芽腫"別冊 日本臨床 領域症候群シリーズ. 28. 169-172 (2000)

Hiroshi Kanno：“血管母细胞瘤”特卷日本临床领域综合征系列。28. 169-172 (2000)