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Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits.

Cell | Jan 17, 2013

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.

Pubmed ID: 23313552 RIS Download

Mesh terms: Animals | Cell Differentiation | Cell Line | Cell Lineage | Down-Regulation | Fibroblasts | Humans | Mice | MicroRNAs | Neurons | Polypyrimidine Tract-Binding Protein | RNA Splicing | Synapses

Research resources used in this publication

Data used in this publication

Associated grants

  • Agency: NHGRI NIH HHS, Id: HG004659
  • Agency: NIGMS NIH HHS, Id: R01 GM052872
  • Agency: NHGRI NIH HHS, Id: R01 HG004659
  • Agency: NIGMS NIH HHS, Id: GM052872
  • Agency: NEI NIH HHS, Id: EY021374
  • Agency: NIGMS NIH HHS, Id: GM049369
  • Agency: NIGMS NIH HHS, Id: R01 GM049369

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