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Abstract
Hox genes control many developmental events along the AP axis, but few target genes
have been identified. Whether target genes are activated or repressed, what enhancer
elements are required for regulation, and how different domains of the Hox proteins
contribute to regulatory specificity are poorly understood. Six2 is genetically downstream
of both the Hox11 paralogous genes in the developing mammalian kidney and Hoxa2 in
branchial arch and facial mesenchyme. Loss-of-function of Hox11 leads to loss of Six2
expression and loss-of-function of Hoxa2 leads to expanded Six2 expression. Herein
we demonstrate that a single enhancer site upstream of the Six2 coding sequence is
responsible for both activation by Hox11 proteins in the kidney and repression by
Hoxa2 in the branchial arch and facial mesenchyme in vivo. DNA-binding activity is
required for both activation and repression, but differential activity is not controlled
by differences in the homeodomains. Rather, protein domains N- and C-terminal to the
homeodomain confer activation versus repression activity. These data support a model
in which the DNA-binding specificity of Hox proteins in vivo may be similar, consistent
with accumulated in vitro data, and that unique functions result mainly from differential
interactions mediated by non-homeodomain regions of Hox proteins.