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Stem Cell Reports. 2014 Aug 12;3(2):282-96. doi: 10.1016/j.stemcr.2014.05.020. Epub 2014 Jul 4.

Generation of induced neuronal cells by the single reprogramming factor ASCL1.

Author information

1
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
2
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
3
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University, Stanford, CA 94305, USA.
4
Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
5
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
6
Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: tcs1@stanford.edu.
7
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University, Stanford, CA 94305, USA. Electronic address: wernig@stanford.edu.

Abstract

Direct conversion of nonneural cells to functional neurons holds great promise for neurological disease modeling and regenerative medicine. We previously reported rapid reprogramming of mouse embryonic fibroblasts (MEFs) into mature induced neuronal (iN) cells by forced expression of three transcription factors: ASCL1, MYT1L, and BRN2. Here, we show that ASCL1 alone is sufficient to generate functional iN cells from mouse and human fibroblasts and embryonic stem cells, indicating that ASCL1 is the key driver of iN cell reprogramming in different cell contexts and that the role of MYT1L and BRN2 is primarily to enhance the neuronal maturation process. ASCL1-induced single-factor neurons (1F-iN) expressed mature neuronal markers, exhibited typical passive and active intrinsic membrane properties, and formed functional pre- and postsynaptic structures. Surprisingly, ASCL1-induced iN cells were predominantly excitatory, demonstrating that ASCL1 is permissive but alone not deterministic for the inhibitory neuronal lineage.

PMID:
25254342
PMCID:
PMC4176533
DOI:
10.1016/j.stemcr.2014.05.020
[Indexed for MEDLINE]
Free PMC Article

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