THE HUMAN SUCRASE-ISOMALTASE GENE DIRECTS COMPLEX PATTERNS OF GENE-EXPRESSION IN TRANSGENIC MICE

Sucrase-isomaltase (SI) is an enterocyte-specific gene that is expressed in complex developmental and spatial patterns. In this study, we examine the ability of regulatory elements within the human SI (hSI) gene to direct appropriate cell lineage and spatial patterns of expression in transgenic mice. Transgenic mouse lines were established using a construct containing bases -3424 to +54 of the hSI gene linked to the human growth hormone (hGH) structural gene. In each transgenic line, hGH mRNA and protein were expressed only in the small intestine and colon. In contrast to the endogenous mouse SI (mSI) gene, which was expressed along the entire length of the small intestine, hGH mRNA expression was predominantly found in the distal jejunum and ileum, with very low levels in more proximal portions of the small intestine. However, the pattern of transgene expression along the small intestinal crypt-villus axis was identical to the pattern of the endogenous mSI gene. These results suggest that regulatory elements necessary for intestine-specific transcription and differential expression along the intestinal crypt-villus axis are included in the 5'-flanking region of the hSI gene. Furthermore, these data suggest that different DNA regulatory regions regulate transcription along the horizontal intestinal axis. In the colon, there was aberrant expression of hGH in a subpopulation of enteroendocrine cells that contained peptide tyrosine tyrosine (PYY). This suggests that there are DNA regulatory elements, missing in the transgene construct, which normally suppress expression of the endogenous mSI gene in these cells. Taken together, these findings define the SI gene as a useful model for studies of differentiation, cell lineage determination, and mechanisms of complex spatial gene expression in the intestine.