During the evolution of insects from a millipede-like ancestor, the Ho
x genes are thought to have promoted the diversification of originally
identical body structures(1,2). In Drosophila melanogaster ter, anten
nae and legs are homologous structures that differ from each other as
a result of the Hox gene Antennapedia (Antp), which promotes leg ident
ities by repressing unknown antennal-determining genes(3-7). Here we p
resent four lines of evidence that identify extradenticle (exd) and ho
mothorax (hth) as antennal-determining genes. First, removing the func
tion of exd(8,9) or hth, which is required for the nuclear localizatio
n of Exd protein(10), transforms the antenna into leg; such transforma
tions occur without activation of Antp. Second, hth is expressed and E
xd is nuclear in most antennal cells, whereas both are restricted to p
roximal cells of the leg. Third, Antp is a repressor of hth. Fourth, e
ctopic expression of Meisl, a murine hth homologue(10), can trigger an
tennal development elsewhere in the fly. Taken together, these data in
dicate that hth is an antennal selector gene, and that Antp promotes l
eg development by repressing hth and consequently nuclear Exd.