Fig. 4. Schematic representation of the signal cascade. In early stages of limb development (stages 10 to 12), Tbx5 and Tbx4 activate the Wnt2B/Fgf and Wnt8C/Fgf signals, respectively. Once activated, the Wnt/Fgf cascades feedback on to Tbx5 and Tbx4 genes to establish a tight positive regulatory loop. At later developmental stages, the Wnt and Fgf signaling cascades interact to make a positive feedback loop and maintain outgrowth of limb buds. During later stages, Tbx5 and Tbx4 exert distinct actions to make different limb structures: wing and leg, respectively.