PANCREATIC-ISLET EXPRESSION OF THE HOMEOBOX FACTOR STF-1 RELIES ON ANE-BOX MOTIF THAT BINDS USF

The commitment of cells to specific lineages during development is det ermined in large part by the relative expression of various homeodomai n (HOX) selector proteins, which mediate the activation of distinct ge netic programs. But the mechanisms by which individual HOX genes are t hemselves targeted for expression in different cell types remain large ly uncharacterized. Here, we demonstrate that STF-1, a homeodomain pro tein that functions in pancreatic morphogenesis and in glucose homeost asis is encoded by an ''orphan'' homeobox gene on mouse chromosome 5. When fused to a beta-galactosidase reporter gene, a 6.5-kilobase genom ic fragment of 5'-flanking sequence from the STF-1 gene shows pancreat ic islet specific activity in transgenic mice. Two distinct elements w ithin the STF-1 promoter are required for islet-restricted expression: a distal enhancer sequence located between -3 and -6.5 kilobases and a proximal E-box sequence located at -104, which is recognized primari ly by the helix loop helix/leucine zipper nuclear factor USF. As point mutations within the -104 E-box that disrupt USF binding correspondin gly impair STF-1 promoter activity, our results demonstrate that USF i s an important component of the regulatory apparatus which directs STF -1 expression to pancreatic islet cells.