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Sox2 controls neura...
Sox2 controls neural stem cell self-renewal through a Fos-centered gene regulatory network
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- Pagin, Miriam (author)
- Univ Milano Bicocca, Italy
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- Pernebrink, Mattias (author)
- Linköpings universitet,Avdelningen för molekylär medicin och virologi,Medicinska fakulteten
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- Giubbolini, Simone (author)
- Univ Milano Bicocca, Italy
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- Barone, Cristiana (author)
- Univ Milano Bicocca, Italy
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- Sambruni, Gaia (author)
- Univ Milano Bicocca, Italy
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- Zhu, Yanfen (author)
- Jackson Lab Genom Med, CT USA
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- Chiara, Matteo (author)
- Univ Milan, Italy
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- Ottolenghi, Sergio (author)
- Univ Milano Bicocca, Italy
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- Pavesi, Giulio (author)
- Univ Milan, Italy
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- Wei, Chia-Lin (author)
- Jackson Lab Genom Med, CT USA
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- Cantù, Claudio, 1981- (author)
- Linköpings universitet,Avdelningen för molekylär medicin och virologi,Medicinska fakulteten
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- Nicolis, Silvia K. (author)
- Univ Milano Bicocca, Italy
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(creator_code:org_t)
- 2021-03-29
- 2021
- English.
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In: Stem Cells. - : WILEY. - 1066-5099 .- 1549-4918. ; 39:8, s. 1107-1119
- Related links:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
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- The Sox2 transcription factor is necessary for the long-term self-renewal of neural stem cells (NSCs). Its mechanism of action is still poorly defined. To identify molecules regulated by Sox2, and acting in mouse NSC maintenance, we transduced, into Sox2-deleted NSC, genes whose expression is strongly downregulated following Sox2 loss (Fos, Jun, Egr2), individually or in combination. Fos alone rescued long-term proliferation, as shown by in vitro cell growth and clonal analysis. Furthermore, pharmacological inhibition by T-5224 of FOS/JUN AP1 complex binding to its targets decreased cell proliferation and expression of the putative target Suppressor of cytokine signaling 3 (Socs3). Additionally, Fos requirement for efficient long-term proliferation was demonstrated by the reduction of NSC clones capable of long-term expansion following CRISPR/Cas9-mediated Fos inactivation. Previous work showed that the Socs3 gene is strongly downregulated following Sox2 deletion, and its re-expression by lentiviral transduction rescues long-term NSC proliferation. Fos appears to be an upstream regulator of Socs3, possibly together with Jun and Egr2; indeed, Sox2 re-expression in Sox2-deleted NSC progressively activates both Fos and Socs3 expression; in turn, Fos transduction activates Socs3 expression. Based on available SOX2 ChIPseq and ChIA-PET data, we propose a model whereby Sox2 is a direct activator of both Socs3 and Fos, as well as possibly Jun and Egr2; furthermore, we provide direct evidence for FOS and JUN binding on Socs3 promoter, suggesting direct transcriptional regulation. These results provide the basis for developing a model of a network of interactions, regulating critical effectors of NSC proliferation and long-term maintenance.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- AP1 inhibitor T‐ 5224; CRISPR; CUT& RUN; Fos; lentiviral vector; neural stem cells (NSCs); self‐ renewal; Socs3; Sox2; transcription factors
Publication and Content Type
- ref (subject category)
- art (subject category)
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Stem Cells
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- By the author/editor
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Pagin, Miriam
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Pernebrink, Matt ...
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Giubbolini, Simo ...
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Barone, Cristian ...
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Sambruni, Gaia
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Zhu, Yanfen
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show more...
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Chiara, Matteo
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Ottolenghi, Serg ...
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Pavesi, Giulio
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Wei, Chia-Lin
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Cantù, Claudio, ...
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Nicolis, Silvia ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
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Stem Cells
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Linköping University