Significance Because structures in the developing embryo are organized by secreted signals, embryonic cells must integrate multiple inputs to turn on the target genes necessary for proper development. Little is known about how multiple signals can work together to regulate such target genes in an embryological context. In this work, we use cultured limb bud mesenchymal cells to investigate how two such signals, Sonic hedgehog (Shh) and fibroblast growth factor 8 (Fgf8), work together to control the activity of Hoxd genes, a set of transcription factors necessary for the patterning of developing tetrapod limbs.