Direct conversion of fibroblasts to functional neurons by defined factors

Nature. 2010 Feb 25;463(7284):1035-41. doi: 10.1038/nature08797. Epub 2010 Jan 27.

Abstract

Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modelling and regenerative medicine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Biomarkers / analysis
  • Cell Line
  • Cell Lineage*
  • Cell Transdifferentiation*
  • Cells, Cultured
  • Embryo, Mammalian / cytology
  • Fibroblasts / cytology*
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology*
  • Neurons / metabolism
  • Neurons / physiology*
  • Oligodendrocyte Transcription Factor 2
  • POU Domain Factors / genetics
  • POU Domain Factors / metabolism
  • Regenerative Medicine
  • Synapses / metabolism
  • Tail / cytology
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers
  • Nerve Tissue Proteins
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2
  • POU Domain Factors
  • Transcription Factors
  • Zic1 protein, mouse
  • Pou3f2 protein, mouse