Actions of betacellulin in the gastrointestinal tract [thesis]

Maik Dahlhoff
2009
This work employed a transgenic mouse model to investigate the functions and effects elicited by the peptide growth factor betacellulin (BTC), an EGFR ligand, on the physiology and pathology of the gastrointestinal tract. BTC, a 32-kDa glycosylated protein, was initially purified from a mouse pancreatic β-cell carcinoma cell line. In addition to the EGFR, BTC is also able to directly bind and activate the related ERBB4 receptor. BTC is expressed in a wide variety of tissues, particularly in the
more » ... particularly in the pancreatic β-cells, stomach, small intestine, lung, kidney and uterus. Three different transgenic mouse lines (L2, L4, and L5) overexpressing BTC under the control of a ubiquitous promoter were established by pronuclear DNA microinjection. Southern blot analysis revealed different integration sites for each line. RT-PCR, Northern and Western blot analysis revealed strong expression of the transgene in the lung, heart, brain and pancreas, with detectable levels in other tissues like stomach, intestine, muscle, bones, liver, thymus, spleen, kidneys, adrenal glands, ovaries, brain and eyes of transgenic mice. BTC-transgenic mice showed stunted growth and significantly reduced relative pancreas and carcass weights. In contrast, the absolute and relative weights of eyes, lung, stomach, intestine and spleen were significantly increased. BTC-transgenic mice exhibit a remarkable, age-dependent hyperplasia of the gastric epithelium. The lesions were characterized by a tumor-like hyperplasia of foveolar epithelium with large cystic formations and a severe depletion of the preexisting body of the mucosa, thus resembling some aspects of human gastric tumors found in patients with Ménétrier disease where TGFA, another ligand of the EGFR, plays an important role. BTC-transgenic animals showed hypoalbuminemia (due to protein loss across the mucosa) and an increase in the gastric pH (as a consequence of parietal cell depletion), while gastrin levels were not altered. The hyperplastic lesions originated exclusively in the lesser curvature [...]
doi:10.5282/edoc.9846 fatcat:tagao227dfhv3m4fl3aq536xse