Inhibition of WNT/β-catenin is necessary and sufficient to induce Scx expression in developing tendons of chicken limb

The cell differentiation of the musculoskeletal system is highly coordinated during limb development. In the distal-most region of the limb, WNT and FGF released from the apical ectodermal ridge maintain mesenchymal cells in the undifferentiated stage. Once the cells stop receivingWNT and FGF, they respond to differentiation signals. Particularly during tendon development, mesenchymal cells enter the cell differentiation program once Scleraxis (Scx) gene expression occurs. Among the signals that trigger the cell differentiation programs, TGF beta signaling has been found to be closely involved in tendon differentiation. However, whether Scx gene expression depends merely on TGF beta signaling or other signals is still not fully understood. In the present study, considering that WNT/beta-catenin is an inhibitory signal of cell differentiation, we speculated possible antagonistic or additive effects between canonical Wnt/beta-catenin and TGF beta/SMAD signaling pathways to control Scx gene expression. We found that the blockade of WNT/beta-catenin promoted Scx gene expression. In contrast, the inhibition of TGF beta/SMAD signaling did not maintain Scx gene expression. Interestingly, the blockade of both WNT/beta-catenin and TGF beta/SMAD signaling at the same time promoted Scx gene expression.Thus the inhibition of WNT/beta-catenin signaling appears to be necessary and sufficient to induce Scx gene expression.

Automated summary

Cell differentiation in the musculoskeletal system is highly coordinated during limb development, with WNT and FGF signals maintaining undifferentiated mesenchymal cells while TGF beta is closely involved in tendon differentiation. In this study, the inhibition of WNT signaling promoted Scx gene expression, and simultaneously blocking both WNT and TGF beta signals further enhanced Scx gene expression. These findings suggest that inhibition of WNT signaling is necessary and sufficient to induce Scx gene expression.