SOXF factors regulate murine satellite cell self-renewal and function through inhibition of β-catenin activity

Abstract

Muscle satellite cells are the primary source of stem cells for postnatal skeletal muscle growth and regeneration. Understanding genetic control of satellite cell formation, maintenance, and acquisition of their stem cell properties is on-going, and we have identified SOXF (SOX7, SOX17, SOX18) transcriptional factors as being induced during satellite cell specification. We demonstrate that SOXF factors regulate satellite cell quiescence, self-renewal and differentiation. Moreover, ablation of Sox17 in the muscle lineage impairs postnatal muscle growth and regeneration. We further determine that activities of SOX7, SOX17 and SOX18 overlap during muscle regeneration, with SOXF transcriptional activity requisite. Finally, we show that SOXF factors also control satellite cell expansion and renewal by directly inhibiting the output of β-catenin activity, including inhibition of Ccnd1 and Axin2. Together, our findings identify a key regulatory function of SoxF genes in muscle stem cells via direct transcriptional control and interaction with canonical Wnt/β-catenin signaling.

PAX3 Confers Functional Heterogeneity in Skeletal Muscle Stem Cell Responses to Environmental Stress

“…PAX3 protein expression was detected in GFP + MuSCs from both isolated biceps myofibers and plated PAX7 + GFP + MuSCs from control (Pax3 Ctrl) mice (Figures 2D and 2E). We did not observe any PAX3 expression elsewhere in skeletal muscle (Alonso-Martin et al, 2018). This specific PAX3 expression was lost in GFP-traced cells from Pax7 creERT2/+ : Pax3 GFP/flox (Pax3 cKO) mice (Figures 2D and 2E).…”

SoxGenes Show Spatiotemporal Expression during Murine Tongue and Eyelid Development

“…It is possible that the different expression patterns of Sox genes in tongue muscles could be correlated with the onset of these stages, although the molecular mechanisms regulating the initiation of each phase during tongue development remain unclear. It has been shown that Sox7, 15, 17 and 18 are involved in the function of satellite cells after birth, although these are not exerted at embryonic stages [ 11 – 13 ]. Therefore, a punctate expression pattern of Sox7, 17, and 18 observed in the embryonic tongue are likely to represent vascularization of the tissue.…”

Sox17 Promotes Oligodendrocyte Regeneration by Dual Modulation of Hedgehog and Wnt Signaling

“…Similar to Sox9 in chondrocytes ( Topol et al., 2009 ), Sox17 overexpression was found to increase beta-catenin phosphorylation in adult WM, reducing unphosphorylated, stabilized beta-catenin. In other systems, Sox17 also regulates muscle satellite cell expansion and renewal by inhibiting beta-catenin activity ( Alonso-Martin et al., 2018 ). Strikingly, both beta-catenin and ABC in Olig2 cells were suppressed by SAG in Sox17CKO ( Figures 7 F and 7G), indicating that Sox17-expressing oligodendroglia rely on Smoothened to regulate beta-catenin abundance and activity through the same pathway.…”

“…Similar to Sox9 in chondrocytes (Topol et al, 2009), Sox17 overexpression was found to increase beta-catenin phosphorylation in adult WM, reducing unphosphorylated, stabilized beta-catenin. In other systems, Sox17 also regulates muscle satellite cell expansion and renewal by inhibiting beta-catenin activity (Alonso-Martin et al, 2018 through the same pathway. The finding that total ABC-expressing cells were not suppressed by SAG in Sox17deficient lesions reveals a cell-specific, Sox17-dependent component of ABC control.…”