title: Neural stem cell differentiation is dictated by distinct actions of nuclear receptor corepressors and histone deacetylases.
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.
authors.affiliation: 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.
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Castelo-Branco
authors.affiliation: Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Lilja
authors.affiliation: Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Wallenborg
authors.affiliation: 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.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Falcão
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Sueli C
authors.initials: SC
authors.lastname: Marques
authors.affiliation: Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Aileen
authors.initials: A
authors.lastname: Gracias
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093-0648, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Solum
authors.affiliation: Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Paap
authors.affiliation: Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Julian
authors.initials: J
authors.lastname: Walfridsson
authors.affiliation: Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Teixeira
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093-0648, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093-0648, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Jepsen
authors.affiliation: Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: ola.hermanson@ki.se.
authors.forename: Ola
authors.initials: O
authors.lastname: Hermanson
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056970:Co-Repressor Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis; D011401:Promoter Regions, Genetic; D051381:Rats; D055757:SOXE Transcription Factors / Q000235:genetics; D000099186:Histone Deacetylase 3
chemical_list: D056970:Co-Repressor Proteins; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D055757:SOXE Transcription Factors; D000099186:Histone Deacetylase 3; C527925:Sox10 protein, rat