In vivo analysis of mouse gastrin gene regulation in enhanced GFP-BAC transgenic mice.
Gastrin is secreted from a subset of neuroendocrine cells residing in the gastric antrum known as G cells, but low levels are also expressed in fetal pancreas and intestine and in many solid malignancies. Although past studies have suggested that antral gastrin is transcriptionally regulated by inflammation, gastric pH, somatostatin, and neoplastic transformation, the transcriptional regulation of gastrin has not previously been demonstrated in vivo. Here, we describe the creation of an enhanced green fluorescent protein reporter (mGAS-EGFP) mouse using a bacterial artificial chromosome that contains the entire mouse gastrin gene. Three founder lines expressed GFP signals in the gastric antrum and the transitional zone to the corpus. In addition, GFP(+) cells could be detected in the fetal pancreatic islets and small intestinal villi, but not in these organs of the adult mice. The administration of acid-suppressive reagents such as proton pump inhibitor omeprazole and gastrin/CCK-2 receptor antagonist YF476 significantly increased GFP signal intensity and GFP(+) cell numbers in the antrum, whereas these parameters were decreased by overnight fasting, octreotide (long-lasting somatostatin ortholog) infusion, and Helicobacter felis infection. GFP(+) cells were also detected in the anterior lobe of the pituitary gland and importantly in the colonic tumor cells induced by administration with azoxymethane and dextran sulfate sodium salt. This transgenic mouse provides a useful tool to study the regulation of mouse gastrin gene in vivo, thus contributing to our understanding of the mechanisms involved in transcriptional control of the gastrin gene.
Division of Digestive and Liver Disease, Dept. of Medicine, Columbia Univ. Medical Center, 1130 St. Nicholas Ave., ICRC 923, New York, NY, USA. tcw21@columbia.edu
Shigeo
S
Takaishi
Wataru
W
Shibata
Hiroyuki
H
Tomita
Guangchun
G
Jin
Xiangdong
X
Yang
Russell
R
Ericksen
Zinaida
Z
Dubeykovskaya
Samuel
S
Asfaha
Michael
M
Quante
Kelly S
KS
Betz
Arthur
A
Shulkes
Timothy C
TC
Wang
D000375:Aging / Q000378:metabolism; D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D015536:Down-Regulation; D005215:Fasting; D005333:Fetus / Q000378:metabolism; D005744:Gastric Acid / Q000378:metabolism; D019863:Gastrin-Secreting Cells / Q000378:metabolism*; D005755:Gastrins / Q000172:deficiency / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics* / Q000378:metabolism; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism; D044922:Helicobacter felis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D011706:Pyloric Antrum / Q000378:metabolism / Q000473:pathology; D013004:Somatostatin / Q000008:administration & dosage; D014018:Tissue Distribution; D014158:Transcription, Genetic; D019076:Transgenes; D015854:Up-Regulation
D002273:Carcinogens; D005755:Gastrins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D013004:Somatostatin; D016264:Dextran Sulfate; D001397:Azoxymethane