Direct Conversion of Fibroblasts to Neurons by Reprogramming PTB-Regulated MicroRNA Circuits

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• 作者：Yuanchao Xue¹ ; ² ; Kunfu Ouyang³ ; Jie Huang¹ ; Yu Zhou¹ ; ² ; Hong Ouyang⁴ ; Hairi Li² ; Gang Wang³ ; Qijia Wu¹ ; Chaoliang Wei² ; Yanzhen Bi¹ ; Li Jiang¹ ; Zhiqiang Cai¹ ; Hui Sun¹ ; Kang Zhang⁴ ; Yi Zhang¹ ; ⁵ ; Ju Chen³ ; Xiang-Dong Fu¹ ; ² ; ⁴ ; ^{xdfu@ucsd.edu}
• 刊名：Cell
• 出版年：2013
• 出版时间：17 January, 2013
• 年：2013
• 卷：152
• 期：1-2
• 页码：82-96
• 全文大小：3032 K

文摘

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Summary

The induction of pluripotency or trans-differentiation of one cell type to another can be accomplished with cell-lineage-specific transcription factors. Here, we report that repression of a single RNA binding polypyrimidine-tract-binding (PTB) protein, which occurs during normal brain development via the action of miR-124, is sufficient to induce trans-differentiation of fibroblasts into functional neurons. Besides its traditional role in regulated splicing, we show that PTB has a previously undocumented function in the?regulation of microRNA functions, suppressing or enhancing microRNA targeting by competitive binding on target mRNA or altering local RNA secondary structure. A key event during neuronal induction is the relief of PTB-mediated blockage of microRNA action on multiple components of the REST complex, thereby derepressing a large array of neuronal genes, including miR-124 and multiple neuronal-specific transcription factors, in nonneuronal cells. This converts a negative feedback loop to a positive one to elicit cellular reprogramming to the neuronal lineage.