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Stem Cell Reports. 2014 Sep 9;3(3):502-15. doi: 10.1016/j.stemcr.2014.07.008. Epub 2014 Aug 28.

Neural stem cell differentiation is dictated by distinct actions of nuclear receptor corepressors and histone deacetylases.

Author information

1
Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden; Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: goncalo.castelo-branco@ki.se.
2
Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
3
Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden; Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
4
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
5
Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093-0648, USA.
6
Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: ola.hermanson@ki.se.

Abstract

Signaling factors including retinoic acid (RA) and thyroid hormone (T3) promote neuronal, oligodendrocyte, and astrocyte differentiation of cortical neural stem cells (NSCs). However, the functional specificity of transcriptional repressor checkpoints controlling these differentiation programs remains unclear. Here, we show by genome-wide analysis that histone deacetylase (HDAC)2 and HDAC3 show overlapping and distinct promoter occupancy at neuronal and oligodendrocyte-related genes in NSCs. The absence of HDAC3, but not HDAC2, initiated a neuronal differentiation pathway in NSCs. The ablation of the corepressor NCOR or HDAC2, in conjunction with T3 treatment, resulted in increased expression of oligodendrocyte genes, revealing a direct HDAC2-mediated repression of Sox8 and Sox10 expression. Interestingly, Sox10 was required also for maintaining the more differentiated state by repression of stem cell programming factors such as Sox2 and Sox9. Distinct and nonredundant actions of NCORs and HDACs are thus critical for control of lineage progression and differentiation programs in neural progenitors.

PMID:
25241747
PMCID:
PMC4266002
DOI:
10.1016/j.stemcr.2014.07.008
[Indexed for MEDLINE]
Free PMC Article

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