Sox2 controls neural stem cell self-renewal through a Fos-centered gene regulatory network.

Publisher: Oxford University Press Country of Publication: England NLM ID: 9304532 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1549-4918 (Electronic) Linking ISSN: 10665099 NLM ISO Abbreviation: Stem Cells Subsets: MEDLINE

Publication: 2022- : Oxford : Oxford University Press
Original Publication: Dayton, OH : AlphaMed Press, c1993-

Neural Stem Cells*/metabolism ; Proto-Oncogene Proteins c-fos*/genetics ; Proto-Oncogene Proteins c-fos*/metabolism ; SOXB1 Transcription Factors*/genetics ; SOXB1 Transcription Factors*/metabolism; Animals ; Cell Proliferation/genetics ; Cell Self Renewal/genetics ; Gene Expression Regulation ; Gene Regulatory Networks ; Mice ; Suppressor of Cytokine Signaling 3 Protein/genetics ; Suppressor of Cytokine Signaling 3 Protein/metabolism

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.
(© 2021 AlphaMed Press.)

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Keywords: AP1 inhibitor T-5224; CRISPR; CUT&RUN; Fos; Socs3; Sox2; lentiviral vector; neural stem cells (NSCs); self-renewal; transcription factors

0 (Fos protein, mouse)
0 (Proto-Oncogene Proteins c-fos)
0 (SOXB1 Transcription Factors)
0 (Suppressor of Cytokine Signaling 3 Protein)

Date Created: 20210319 Date Completed: 20220310 Latest Revision: 20220531

20231215

10.1002/stem.3373

33739574