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

Sox2 is necessary for long ‐term NSC self‐renewal and for Socs3, Fos, Jun and Egr2 gene expression. We previously showed that Socs3 overexpression rescues Sox2‐deleted NSC self‐renewal. Fos, Jun and Egr2 transduction into Sox2‐deleted NSC rescues self‐renewal, Fos alone being both sufficient and necessary. Sox2 tr ansduction upregulates Fos and Socs3 in Sox2‐deleted cells, and Fos upregulates Socs3, defining a Sox2‐dependent regulatory network. AbstractThe Sox2 transcription factor is necessary for the long ‐term self‐renewal of neural stem cells (NSC). 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, Eg r2), individually or in combination. Fos alone rescued long‐term proliferation, as shown by in vitro cell growth and clonal analysis. Further, pharmacological inhibition by T‐5224 of FOS/JUN AP1 complex binding to its targets decreased cell proliferation and expression of the putative target Sup pressor 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 down regulated following Sox2 deletion, and its reexpression by lentivira...
Source: Stem Cells - Category: Stem Cells Authors: Tags: Tissue ‐Specific Stem Cells Source Type: research