A transgenic mouse model that is useful for analyzing cellular and geographic differentiation of the intestine during fetal development.
Regional as well as cell-specific differences in gene expression are established and maintained in the perpetually regenerating intestinal epithelium. We have recently linked regions of the 5'-nontranscribed domain of the rat "liver" fatty acid binding protein (L-FABP) gene which is normally expressed in both liver and intestine, to a reporter, the human growth hormone (hGH) gene, and examined hGH expression in adult transgenic mice (Sweetser, D. A., Birkenmeier, E. H., Hoppe, P. C., McKeel, D. W., and Gordon, J. I. (1988) Genes Dev. 2, 1318-1332). Our results indicated that cis-acting elements, including an orientation-independent suppressor, could produce a pattern of cellular and geographic expression of hGH which mimics that of the intact, endogenous murine Fabpl gene in both organs. We now show that nucleotides -4000 to +21 of the rat L-FABP gene can direct "appropriate" cell-specific, regional, and temporal expression of the hGH reporter during a period of remarkable cellular expansion, cytodifferentiation, and morphologic transformation of the fetal gut epithelium. These studies also indicate that the polyclonal stem cell population located in the intervillous regions of the late fetal intestine exhibits a different pattern of transgene regulation than does the monoclonally derived crypt stem cell population in adult transgenic mice. Nucleotides -4000 to +21 are not sufficient to reproduce the normal temporal pattern of L-FABP gene activation in liver. Precocious expression of growth hormone in this pedigree of transgenic mice results in early induction of insulin-like growth factor I mRNA accumulation in liver but has no effect on insulin-like growth factor II mRNA levels. In contrast, local synthesis of growth hormone in the small intestine does not influence its insulin-like growth factor I or II mRNA levels.
Hauft
S M
SM
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
Sweetser
D A
DA
Rotwein
P S
PS
Lajara
R
R
Hoppe
P C
PC
Birkenmeier
E H
EH
Gordon
J I
JI
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002454:Cell Differentiation; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005786:Gene Expression Regulation; D005865:Gestational Age; D013006:Growth Hormone / Q000235:genetics*; D006651:Histocytochemistry; D007124:Immunoenzyme Techniques; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000196:embryology*; D008099:Liver / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D014018:Tissue Distribution; D015533:Transcriptional Activation
D002352:Carrier Proteins; C493319:FABP1 protein, human; C493320:Fabp1 protein, mouse; C493321:Fabp1 protein, rat; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D013006:Growth Hormone