Zhou Di, Zhang Zhen, He Li-Ming, Du Juan, Zhang Fan, Sun Chong-Kui, Zhou Yu, Wang Xiao-Wei, Lin Ge, Song Ke-Ming, Wu Ling-Gang, Yang Qin
Cancer Biology Division, Washington University School of Medicine, Saint Louis, MO 63108, USA.
Synaptic Transmission Section, NINDS/NIH, Bethesda, MD 20892, USA.
Cell Rep. 2014 Dec 24;9(6):2034-42. doi: 10.1016/j.celrep.2014.11.040. Epub 2014 Dec 18.
Conversion from fibroblasts to neurons has recently been successfully induced. However, the underlying mechanisms are poorly understood. Here, we find that depletion of p53 alone converts fibroblasts into all three major neural lineages. The induced neuronal cells express multiple neuron-specific proteins and generate action potentials and transmitter-receptor-mediated currents. Surprisingly, depletion does not affect the well-known tumorigenic p53 target, p21. Instead, knockdown of p53 upregulates neurogenic transcription factors, which in turn boosts fibroblast-neuron conversion. p53 binds the promoter of the neurogenic transcription factor Neurod2 and regulates its expression during fibroblast-neuron conversion. Furthermore, our method provides a high efficiency of conversion in late-passage fibroblasts. Genome-wide transcriptional analysis shows that the p53-deficiency-induced neurons exhibit an expression profile different from parental fibroblasts and similar to control-induced neurons. The results may help to understand and improve neural conversion mechanisms to develop robust neuron-replacement therapy strategies.
最近已成功诱导成纤维细胞转化为神经元。然而，其潜在机制仍知之甚少。在这里，我们发现单独缺失p53可将成纤维细胞转化为所有三种主要神经谱系。诱导产生的神经元细胞表达多种神经元特异性蛋白，并产生动作电位和递质-受体介导的电流。令人惊讶的是，缺失p53并不影响众所周知的肿瘤抑制p53靶点p21。相反，敲低p53会上调神经源性转录因子，进而促进成纤维细胞向神经元的转化。p53结合神经源性转录因子Neurod2的启动子，并在成纤维细胞向神经元转化过程中调节其表达。此外，我们的方法在传代后期的成纤维细胞中提供了高效率的转化。全基因组转录分析表明，p53缺陷诱导的神经元表现出与亲代成纤维细胞不同但与对照诱导的神经元相似的表达谱。这些结果可能有助于理解和改进神经转化机制，以制定强有力的神经元替代治疗策略。
