Differential expression of the neurotensin gene in the developing rat and human gastrointestinal tract

Abstract

Neurotensin (NT) is an important hormone regulating gut motility, secretion, and growth. The purpose of this study was to determine the developmental expression of the NT/neuromedin N gene (NT/N) in the gut and pancreas of rats and humans. We found that NT/N expression, initially low in the fetal rat jejunum and ileum, is increased by postnatal day 3. This increase is independent of contact with luminal nutrients as demonstrated by elevated NT/N expression in rat jejunoileal grafts implanted in nude mice. NT/N expression reaches maximal levels in the small bowel by postnatal day 14. After postnatal day 28, NT/N mRNA levels remain constant in the ileum but decrease in the jejunum. Transient NT/N expression is found in the colon of fetal and postnatal rats. Similar to the rat, NT/N expression is low in the human fetal ileum but increases in the adult. In the human colon, NT/N is transiently expressed in the fetus at midgestation but disappears by birth and, similarly, is not apparent in the adult. We conclude the following. 1) The NT/N gene demonstrates a complex pattern of tissue-specific expression; the jejunum and ileum show a similar pattern of expression until the end of the fourth postnatal week, when NT/N levels decrease in the jejunum to assume the distinctive adult topographical distribution with NT/N increasing along the jejunoileal axis. 2) NT/N is transiently expressed in the colon of rats and humans during a developmental stage characterized by morphological and functional similarities to the small bowel; therefore, NT/N may provide a useful endocrine marker to further define the complex differentiation pathway leading to small bowel and colonic phenotypes.

Characterization of Promoter Elements Regulating the Expression of the Human Neurotensin/Neuromedin N Gene

“…The primary sequences of both the rat and human genes encoding NT and the structurally related hexapeptide, neuromedin N, have been elucidated (19,20). In the GI tract, the NT/neuromedin N (NT/N) gene is developmentally regulated in the human and rat intestines in a temporospatial manner (21)(22)(23). The promoter proximal 5Ј-flanking region of the rat NT/N gene has previously been shown to integrate multiple environmental stimuli in neuroendocrine PC12 cells and to be sufficient for cell-specific expression in enteroendocrine BON cells (24,25).…”

The neurotensin gene is a downstream target for Ras activation.

“…NT facilitates translocation of fatty acids in the proximal including secretion, motility, and gut mucosal growth (28)(29)(30)(31)(32)(33)(34)(35)(36). Expression of the gene encoding NT and the structurally related hexapeptide neuromedin N (designated NT/N) is developmentally regulated in the gut of both rat and human in a distinctive temporal-and spatial-specific distribution (37,38). NT/N expression is initially low in the fetus but rapidly increases after birth to assume the distinctive adult topographical distribution of increasing NT/N expression along the longitudinal axis of the small bowel.…”

“…Using isolated gut segments from the rat implanted as xenografts in athymic nude mice, we recently demonstrated that the strict temporal-and spatial-specific pattern of NT/N expression is not affected by either location or luminal contents, thus suggesting an intrinsic program of NT/N gene expression (39). In the human colon, NT/N is transiently expressed during a developmental stage (midgestation) that is characterized by morphologic and functional similarity to the small bowel (40,41); however, expression of NT/N is not apparent in the colon of the newborn or the adult (37). Taken together, these studies identify the NT/N gene as an important endocrine model to better delineate the complex mechanisms leading to differentiation of the gut to either a small bowel or colonic phenotype.…”

“…These findings indicate that the parental CaCo2 and CaCo2-ras cell lines offer a unique and well-characterized system to further define the cellular mechanisms leading to small bowel differentiation and the regulation of expression of differentiated cellular products of the GI tract, such as the gut hormones, in which little is known about the molecular factors mediating the distinct patterns of cell-specific expression. Expression of the NT/N gene is regulated in a temporaland spatial-specific pattern and is highly dependent on the state of gut differentiation (37,38). For example, NT/N expression is limited in the adult GI tract to the small bowel; however, NT/N is expressed in the fetal colon during midgestation when the colon morphologically resembles the small bowel (37).…”

“…Expression of the NT/N gene is regulated in a temporaland spatial-specific pattern and is highly dependent on the state of gut differentiation (37,38). For example, NT/N expression is limited in the adult GI tract to the small bowel; however, NT/N is expressed in the fetal colon during midgestation when the colon morphologically resembles the small bowel (37). NT/ N is not expressed in the normal colon of the newborn or the adult.…”