Localization of cystic fibrosis transmembrane conductance regulator mRNA in the human gastrointestinal tract by in situ hybridization.

Abstract

We have used in situ hybridization to localize expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in the human gastrointestinal tract and associated organs. The stomach exhibits a low level of CFTR expression throughout gastric mucosa. In the small intestine, expression is relatively high in the mucosal epithelium, with a decreasing gradient of expression along the crypt to tip axis. The cells of the Brunner's glands express high levels of CFTR mRNA. In addition, there is a small subpopulation of highly positive cells scattered along the epithelium in the duodenum and jejunum, but not in the ileum. These cells do not represent endocrine cells, as determined by lack of colocalization with an endocrine-specific marker. The distribution of CFTR mRNA in the colon is similar to the small intestine, with highest level of expression in the epithelial cells at the base of the crypts. In the pancreas, CFIR is expressed at high levels in the small, intercalated ducts and at lower levels in the interlobular ducts. CFI'R transcripts are expressed at uniformly high levels in the epithelium of the gallbladder. Throughout the gastrointestinal tract, CFTR expression is increased in mucosal epithelial cells that are near lymph nodules. (J. Clin. Invest. 1994. 93:347-354.)

The distribution and expression of CFTR restricts electrogenic anion secretion to the ileum of the brushtail possum, Trichosurus vulpecula

“…Within the possum ileum, CFTR is expressed in the crypts and base of the villi, with decreasing levels of expression along the villi and little or no expression in the cells at the tips of the villi. This is very similar to the expression pattern for CFTR in the crypt/villous axis of the eutherian small intestine (Ameen et al, 2000b;Strong et al, 1994;Trezise and Buchwald, 1991), although in the possum ileum we did not see any evidence of the CFTR high expresser (CHE) cells that have been reported in rats and humans (Ameen et al, 1995). However, these CHE cells are restricted to the proximal intestine of rats and humans and are absent in other eutherian mammals (Ameen et al, 2000a).…”

“…This is markedly different from the expression of CFTR in the eutherian intestine, where the highest levels of expression occur in the duodenum with decreasing levels of expression in the jejunum and ileum (Ameen et al, 2000b;Strong et al, 1994;Trezise and Buchwald, 1991). Within the possum ileum, CFTR is expressed in the crypts and base of the villi, with decreasing levels of expression along the villi and little or no expression in the cells at the tips of the villi.…”

WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl − -transporting epithelia

“…Moreover, the distribution of WNK1 expression is notable for its overlap with tissues that show pathology or physiologic defects in cystic fibrosis because of loss of the CFTR gene product (23)(24)(25)(26)(27)(28). These abnormalities in cystic fibrosis include defective Cl Ϫ absorption in sweat ducts (24), impaired pancreatic function caused by inadequate ductal HCO 3 Ϫ secretion with sludging of secretions in exocrine ducts (25), male sterility caused by obstruction and atrophy in the distal epididymis (26), hepatic fibrosis͞cirrhosis caused by inspissated biliary secretions (27), meconium ileus with distal intestinal impaction caused by defective Cl Ϫ transport and abnormal electrolyte absorption in the colon (28), and occasional cases of cholelithiasis caused by deranged gallbladder salt homeostasis (29).…”

“…These abnormalities in cystic fibrosis include defective Cl Ϫ absorption in sweat ducts (24), impaired pancreatic function caused by inadequate ductal HCO 3 Ϫ secretion with sludging of secretions in exocrine ducts (25), male sterility caused by obstruction and atrophy in the distal epididymis (26), hepatic fibrosis͞cirrhosis caused by inspissated biliary secretions (27), meconium ileus with distal intestinal impaction caused by defective Cl Ϫ transport and abnormal electrolyte absorption in the colon (28), and occasional cases of cholelithiasis caused by deranged gallbladder salt homeostasis (29). This striking overlap raises the possibility that WNK1 and CFTR may be involved in shared or parallel physiologic pathways that regulate Cl Ϫ f lux in these epithelia.…”

Intronic enhancers coordinate epithelial-specific looping of the active CFTR locus

“…The CFTR gene encompasses 189 kb at human chromosome 7q31.2 and mutations within it cause the common genetic disease cystic fibrosis (CF) (9). CFTR encodes a membrane-associated chloride ion channel that is expressed at the highest levels in chloride-secreting epithelial cells of the small intestine, pancreas, and male genital duct, and at lower levels in the respiratory epithelium and certain other sites (10)(11)(12)(13)(14). The CFTR promoter has been characterized as a ''housekeeping-like'' promoter and does not posses the regulatory elements responsible for the diverse expression profile of the gene (15)(16)(17).…”