The caudal-related homeobox gene Cdx-2/3 is a critical "master" control gen
e in embryogenesis, Mice heterozygous for a null mutation in Cdx-2/3 exhibi
t multiple malfunctions including tail abnormalities, stunted growth, a hom
eotic shift in vertebrae, and the development of multiple intestinal adenom
atous polyps, indicating that Cdx-2/3 is haplo-insufficient. In vitro studi
es have identified more than a half-dozen downstream target genes expressed
in pancreatic and intestinal cells for this transcription factor, We have
examined the transcriptional properties of the mouse Cdx-2/3 promoter, This
promoter could be autoregulated in pancreatic and intestinal cells that ex
press endogenous Cdx-2/3. In contrast, Cdx-2/3 transfection represses the C
dx-2/3 promoter in fibroblasts, which do not express endogenous Cdx-2/3, Si
nce Cdx-2/3 activates proglucagon gene promoter in both pancreatic and inte
stinal cells and in fibroblasts, we suggest that some, yet to be identified
, cell type-specific components are required for activating selected target
gene promoters of Cdx-2/3, including the Cdx-2/3 promoter itself. Cdx-2/3
binds to the TATA box and another AT-rich motif, designated as DES, within
an evolutionarily conserved proximal element of the Cdx-2/3 promoter. The D
BS motif is critical for the autoregulation, whereas the TATA box may act a
s an attenuating element for the autoregulatory loop. Finally, overexpressi
on of Cdx-2/3 in a pancreatic cell line activated the expression of the end
ogenous Cdx-2/3. Taken together, our results indicate that the dose-depende
nt phenotype of Cdx-2/3 expression on its downstream targets in vivo could
be regulated initially via a transcriptional network involving cell type-sp
ecific autoregulation of the Cdx-2/3 promoter.