Role of Neuronal differentiation and Regeneration of VHL Tumor Suppressor Gene

VHL基因和蛋白在胎儿和成人脑的神经细胞中均有表达。然而，VHL基因在中枢神经系统(CNS)中的作用尚不清楚。VHL基因可能改变了中枢神经系统中胚胎发生和肿瘤发生过程中的各种基因表达。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。在本研究中，我们发现VHL蛋白在中枢神经系统前体细胞中的表达与神经元分化有关，但与神经胶质细胞分化无关，也表明VHL基因转导可以诱导神经元分化。此外，VHLmRNA反义寡核苷酸抑制CNS祖细胞的分化，上调其细胞周期。VHL蛋白在体外可使神经干细胞在电生理功能上转化为成熟的功能神经元，并可分化为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向神经元分化过程中起关键作用。稳定表达VHL蛋白的神经母细胞瘤细胞具有突起样突起，突起呈突起状，突起呈突起突起，突起突起呈突起状突起，突起突起呈突起突起，突起呈突起突起，突起突起呈突起状，突起呈突起突起，突起突起呈突起突起，突起突起呈突起状，突起综上所述，vhl基因在神经元分化过程中起着重要作用，vhl基因诱导细胞是促进神经元再生的有力工具。

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