AN INTESTINE-SPECIFIC HOMEOBOX GENE REGULATES PROLIFERATION AND DIFFERENTIATION

Precise regulation of cellular proliferation, differentiation, and sen escence results in the continuous renewal of the intestinal epithelium with maintenance of a highly ordered tissue architecture, Here we sho w that an intestine-specific homeobox: gene, Cdx2, is a transcription factor that regulates both proliferation and differentiation in intest inal epithelial cells, Conditional expression of Cdx2 in IEC-6 cells, an undifferentiated intestinal cell line, led to arrest of proliferati on for several days followed by a period of growth resulting in multic ellular structures containing a well-formed columnar layer of cells. T he columnar cells had multiple morphological characteristics of intest inal epithelial cells, Enterocyte-like cells were polarized with tight junctions, lateral membrane interdigitations, and well-organized micr ovilli with associated glycocalyx located at the apical pole, Remarkab ly, there were also cells with a goblet cell-like ultrastructure, sugg esting that two of the four intestinal epithelial cell lineages may ar ise from IEC-6 cells, Molecular evidence for differentiation was shown by demonstrating that cells expressing high levels of Cdx2 expressed sucrase-isomaltase, an enterocyte-specific gene which is a well-define d target for the Cdx2 protein, Taken together, our data suggest that C dx2 may play a role in directing early processes in intestinal cell mo rphogenesis and in the maintenance of the differentiated phenotype by supporting transcription of differentiated gene products, We propose t hat Cdx2 is part of a regulatory network that orchestrates a developme ntal program of proliferation, morphogenesis, and gene expression in t he intestinal epithelium.