REPRESSION BY HOXA7 IS MEDIATED BY THE HOMEODOMAIN AND THE MODULATORYACTION OF ITS N-TERMINAL-ARM RESIDUES

Hox genes encode homeodomain containing proteins that are presumed to control spatial patterning during murine embryogenesis through their a ctions as transcriptional regulatory proteins. In this study, we have investigated the transcriptional function of a prototypic member of th is family, HoxA7. We demonstrate that HoxA7 functions as a potent tran scriptional repressor and that its action as such requires several dom ains, including both activator and repressor regions. The repressor re gions are contained within the homeodomain and a C-terminal acidic reg ion, both of which are well conserved among members of the Hox family. Accordingly, we show that two other members of this family also funct ion as repressors, although they vary in their relative repressor pote ncy. Finally, we explore the novel observation that the homeodomain of HoxA7 functions as a transcriptional repressor domain. We show that t he homeodomain compared with two other DNA-binding domains, is unique in its ability to function as a repressor domain and that repression r equires conserved residues in helix III. We further show that residues in the N-terminal arm of the homeodomain contribute to the differenti al repressor actions of various Hox proteins. These findings demonstra te that the transcriptional function of HoxA7 and possibly of Hox prot eins in general is determined by their unique combination of conserved and nonconserved regions as well as through the complex actions of th eir homeodomains.