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Cell Stem Cell. 2015 Jul 2;17(1):74-88. doi: 10.1016/j.stem.2015.05.014. Epub 2015 Jun 25.

Transcriptional Mechanisms of Proneural Factors and REST in Regulating Neuronal Reprogramming of Astrocytes.

Author information

1
Physiological Genomics, Biomedical Center, University of Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Centre Munich, 85764 Neuherberg, Germany.
2
The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK; Hutchison/MRC Research Center, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.
3
Physiological Genomics, Biomedical Center, University of Munich, 80336 Munich, Germany.
4
The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK.
5
Institute of Experimental Genetics, Helmholtz Centre Munich, 85764 Neuherberg, Germany.
6
Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK.
7
Institute of Computational Biology, Helmholtz Centre Munich, 85764 Neuherberg, Germany.
8
Institute of Computational Biology, Helmholtz Centre Munich, 85764 Neuherberg, Germany; Department of Mathematics, Technical University Munich, 85748 Garching, Germany.
9
Institute of Experimental Genetics, Helmholtz Centre Munich, 85764 Neuherberg, Germany; Center of Life and Food Sciences Weihenstephan, Technical University, 85354 Freising, Germany.
10
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, D-55128 Mainz, Germany; Focus Program Translational Neuroscience, Johannes Gutenberg University, D-55128 Mainz, Germany.
11
The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK. Electronic address: francois.guillemot@crick.ac.uk.
12
Physiological Genomics, Biomedical Center, University of Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Centre Munich, 85764 Neuherberg, Germany; Munich Cluster for Systems Neurology "SyNergy," Ludwig Maximilian University of Munich, 80539 Munich, Germany. Electronic address: magdalena.goetz@helmholtz-muenchen.de.

Abstract

Direct lineage reprogramming induces dramatic shifts in cellular identity, employing poorly understood mechanisms. Recently, we demonstrated that expression of Neurog2 or Ascl1 in postnatal mouse astrocytes generates glutamatergic or GABAergic neurons. Here, we take advantage of this model to study dynamics of neuronal cell fate acquisition at the transcriptional level. We found that Neurog2 and Ascl1 rapidly elicited distinct neurogenic programs with only a small subset of shared target genes. Within this subset, only NeuroD4 could by itself induce neuronal reprogramming in both mouse and human astrocytes, while co-expression with Insm1 was required for glutamatergic maturation. Cultured astrocytes gradually became refractory to reprogramming, in part by the repressor REST preventing Neurog2 from binding to the NeuroD4 promoter. Notably, in astrocytes refractory to Neurog2 activation, the underlying neurogenic program remained amenable to reprogramming by exogenous NeuroD4. Our findings support a model of temporal hierarchy for cell fate change during neuronal reprogramming.

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PMID:
26119235
PMCID:
PMC4509553
DOI:
10.1016/j.stem.2015.05.014
[Indexed for MEDLINE]
Free PMC Article

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