A HOMEODOMAIN PROTEIN RELATED TO CAUDAL REGULATES INTESTINE-SPECIFIC GENE-TRANSCRIPTION

The continually renewing epithelium of the intestinal tract arises fro m the visceral endoderm by a series of complex developmental transitio ns. The mechanisms that establish and maintain the processes of cellul ar renewal, cell lineage allocation, and tissue restriction and spatia l assignment of gene expression in this epithelium are unknown. An und erstanding of the regulation of intestine-specific gene regulation may provide information on the molecular mechanisms that direct these pro cesses. In this regard, we show that intestine-specific transcription of sucrase-isomaltase, a gene that is expressed exclusively in differe ntiated enterocytes, is dependent on binding of a tissue-specific home odomain protein (mouse Cdx-2) to an evolutionarily conserved promoter element in the sucrase-isomaltase gene. This protein is a member of th e caudal family of homeodomain genes which appear to function in early developmental events in Drosophila melanogaster, during gastrulation in many species, and in intestinal endoderm. Unique for this homeodoma in gene family, we show that mouse Cdx-2 binds as a dimer to its regul atory element and that dimerization in vitro is dependent on redox pot ential. These characteristics of the interaction of Cdx-2 with its reg ulatory element provide for a number of potential mechanisms for trans criptional regulation. Taken together, these findings suggest that mem bers of the Cdx gene family play a fundamental role both in the establ ishment of the intestinal phenotype during development and in maintena nce of this phenotype via transcriptional activation of differentiated intestinal genes.