DROSOPHILA MAD BINDS TO DNA AND DIRECTLY MEDIATES ACTIVATION OF VESTIGIAL BY DECAPENTAPLEGIC

The TGF-beta (transforming growth factor-beta)-related signalling prot eins, including Decapentaplegic (Dpp) in Drosophila and bone morphogen ic proteins and activin in vertebrates, affect the growth and patterni ng of a great variety of structures. However, the mechanisms by which these ligands regulate gene expression are not understood. Activation of complexes of type I with type II receptors results in the phosphory lation and nuclear localization of members of the SMAD protein family( 1-9), which are thought to act as co-activators of transcription, perh aps in conjunction with sequence-specific cofactors(10). Here we show that the aminoterminal domain of the Drosophila Mothers against dpp pr otein (Mad), a mediator of Dpp signalling(11-14), possesses a sequence -specific DNA-binding activity that becomes apparent when carboxy-term inal residues are removed. Mad binds to and is required for the activa tion of an enhancer within the vestigial wing-patterning gene in cells across the entire developing wing blade. Mad also binds to Dpp-respon se elements in other genes. These results suggest that Dpp signalling regulates gene expression by activating Mad binding to target gene enh ancers.