Model for vertebrate limb induction and outgrowth. During zebrafish fin induction, Tbx5 activates parallel pathways in the lateral plate mesoderm. In one pathway, Tbx5 transcriptionally activiates fgf24, which then initiates a signaling cascade leading to the activation of fgf10. In a second pathway, Tbx5 activity indirectly regulates the expression of fgfr2 (A). During fin outgrowth, Tbx5 transcriptional activity is negatively regulated by Pdlim7-mediated nucleocytoplasmic shuttling. Relocation and retention of Tbx5 at the actin cytoskeleton results in transcriptional restriction of fgf24 in the limb mesenchyme. The mesenchymal downregulation is required for initiating Fgf24 expression in the AER, which is a critical step to establish the reciprocal signaling loop with the mesenchyme to maintain fgf10 and fgfr2 expression (B). Solid arrows denote transcriptional regulation. Dashed arrows indicate signal transduction regulation.