MULTIPLE LEVELS OF CONTROL OF THE STAGE-SPECIFIC AND REGION-SPECIFIC EXPRESSION OF RAT INTESTINAL LACTASE

To elucidate the mechanisms leading to the functional regionalization of the digestive epithelium, lactase expression was analyzed at the pr otein, mRNA and gene levels, along the intestinal tract at various sta ges of the rat postnatal development. In the colon of neonates, the tr ansient expression of mRNA and enzyme correlated well with gene transc ription. In contrast to the colon, complex patterns were observed in t he small intestine. In suckling animals, the mRNA was present at a hig h level despite the progressive decline of enzyme activity. Crypts wer e devoid of mRNA and the transcript mainly accumulated in the lower ha lf of the villi. From weaning onwards, a functional regionalization of the epithelium was defined, characterized by the modification of the longitudinal distribution of lactase mRNA. Indeed the transcript remai ned abundant in the distal duodenum, jejunum and proximal ileum, but d ecreased in the proximal duodenum and became virtually absent in the d istal ileum. Concomitantly, the mRNA and enzyme distribution along the villi changed in the different segments of the small intestine. Patte rns similar to those described in sucklings were retained in the adult jejunum. In contrast, mRNA and enzyme could no longer be detected in the distal ileum, while mosaicism appeared in the proximal duodenum. I n vitro transcription assays carried out with isolated nuclei suggeste d that the decay of lactase mRNA in the proximal duodenum at weaning w as associated with a decreasing rate of transcription of the gene. How ever active gene transcription was retained in the nuclei of the adult jejunum and ileum. The loss of mRNA in the adult distal ileum despite the maintenance of active transcription did not result from an intrag enic block of pre-RNA elongation, as shown by transcription assays car ried out at various positions of the lactase gene. In addition, we loo ked for the ontogenic decline of lactase protein despite the maintenan ce of a high amount of mRNA in the jejunum, and it became evident that the fraction of mRNA present in polysomes was constant with age. Take n together, these data indicate that lactase constitutes an unusual ma rker of development and of functional regionalization of the intestina l tract which exhibits a complex time- and space-specific pattern of g ene, mRNA, and protein expression. The distinct patterns occurring in the duodenum, jejunum, ileum, and the colon of pre- and postweaned rat s depend on a combination of transcriptional, posttranscriptional, and posttranslational levels of regulation, and are associated with a dif ferent mRNA distribution along villi in each intestinal segment.