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FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes

The transcription factor SOX2 is important for brain development and for neural stem cells (NSC) maintenance. Sox2-deleted (Sox2-del) NSC from neonatal mouse brain are lost after few passages in culture. Two highly expressed genes, Fos and Socs3, are strongly downregulated in Sox2-del NSC; we previo...

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Autores principales: Pagin, Miriam, Pernebrink, Mattias, Pitasi, Mattia, Malighetti, Federica, Ngan, Chew-Yee, Ottolenghi, Sergio, Pavesi, Giulio, Cantù, Claudio, Nicolis, Silvia K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303191/
https://www.ncbi.nlm.nih.gov/pubmed/34359927
http://dx.doi.org/10.3390/cells10071757
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author Pagin, Miriam
Pernebrink, Mattias
Pitasi, Mattia
Malighetti, Federica
Ngan, Chew-Yee
Ottolenghi, Sergio
Pavesi, Giulio
Cantù, Claudio
Nicolis, Silvia K.
author_facet Pagin, Miriam
Pernebrink, Mattias
Pitasi, Mattia
Malighetti, Federica
Ngan, Chew-Yee
Ottolenghi, Sergio
Pavesi, Giulio
Cantù, Claudio
Nicolis, Silvia K.
author_sort Pagin, Miriam
collection PubMed
description The transcription factor SOX2 is important for brain development and for neural stem cells (NSC) maintenance. Sox2-deleted (Sox2-del) NSC from neonatal mouse brain are lost after few passages in culture. Two highly expressed genes, Fos and Socs3, are strongly downregulated in Sox2-del NSC; we previously showed that Fos or Socs3 overexpression by lentiviral transduction fully rescues NSC’s long-term maintenance in culture. Sox2-del NSC are severely defective in neuronal production when induced to differentiate. NSC rescued by Sox2 reintroduction correctly differentiate into neurons. Similarly, Fos transduction rescues normal or even increased numbers of immature neurons expressing beta-tubulinIII, but not more differentiated markers (MAP2). Additionally, many cells with both beta-tubulinIII and GFAP expression appear, indicating that FOS stimulates the initial differentiation of a “mixed” neuronal/glial progenitor. The unexpected rescue by FOS suggested that FOS, a SOX2 transcriptional target, might act on neuronal genes, together with SOX2. CUT&RUN analysis to detect genome-wide binding of SOX2, FOS, and JUN (the AP1 complex) revealed that a high proportion of genes expressed in NSC are bound by both SOX2 and AP1. Downregulated genes in Sox2-del NSC are highly enriched in genes that are also expressed in neurons, and a high proportion of the “neuronal” genes are bound by both SOX2 and AP1.
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spelling pubmed-83031912021-07-25 FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes Pagin, Miriam Pernebrink, Mattias Pitasi, Mattia Malighetti, Federica Ngan, Chew-Yee Ottolenghi, Sergio Pavesi, Giulio Cantù, Claudio Nicolis, Silvia K. Cells Article The transcription factor SOX2 is important for brain development and for neural stem cells (NSC) maintenance. Sox2-deleted (Sox2-del) NSC from neonatal mouse brain are lost after few passages in culture. Two highly expressed genes, Fos and Socs3, are strongly downregulated in Sox2-del NSC; we previously showed that Fos or Socs3 overexpression by lentiviral transduction fully rescues NSC’s long-term maintenance in culture. Sox2-del NSC are severely defective in neuronal production when induced to differentiate. NSC rescued by Sox2 reintroduction correctly differentiate into neurons. Similarly, Fos transduction rescues normal or even increased numbers of immature neurons expressing beta-tubulinIII, but not more differentiated markers (MAP2). Additionally, many cells with both beta-tubulinIII and GFAP expression appear, indicating that FOS stimulates the initial differentiation of a “mixed” neuronal/glial progenitor. The unexpected rescue by FOS suggested that FOS, a SOX2 transcriptional target, might act on neuronal genes, together with SOX2. CUT&RUN analysis to detect genome-wide binding of SOX2, FOS, and JUN (the AP1 complex) revealed that a high proportion of genes expressed in NSC are bound by both SOX2 and AP1. Downregulated genes in Sox2-del NSC are highly enriched in genes that are also expressed in neurons, and a high proportion of the “neuronal” genes are bound by both SOX2 and AP1. MDPI 2021-07-12 /pmc/articles/PMC8303191/ /pubmed/34359927 http://dx.doi.org/10.3390/cells10071757 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pagin, Miriam
Pernebrink, Mattias
Pitasi, Mattia
Malighetti, Federica
Ngan, Chew-Yee
Ottolenghi, Sergio
Pavesi, Giulio
Cantù, Claudio
Nicolis, Silvia K.
FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes
title FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes
title_full FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes
title_fullStr FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes
title_full_unstemmed FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes
title_short FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes
title_sort fos rescues neuronal differentiation of sox2-deleted neural stem cells by genome-wide regulation of common sox2 and ap1(fos-jun) target genes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303191/
https://www.ncbi.nlm.nih.gov/pubmed/34359927
http://dx.doi.org/10.3390/cells10071757
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