Developmental Regulation of α-Fetoprotein Expression in Intestinal Epithelial Cells of Transgenic Mice

Abstract

The alpha-fetoprotein (AFP) gene is transcribed in most epithelial cells lining the fetal mouse small intestine, but transcription persists in only a subset of enteroendocrine cells representing less than 1% of the total intestinal epithelial cells in the adult. The decrease in AFP expression after birth is mediated in part by a repressor element lying between -838 and -250 bp of the AFP gene. Deletion of this element from AFP minigene constructs results in high-level minigene expression in the intestines of adult transgenic mice. Although high levels of AFP minigene RNA are expressed, the fetal pattern of expression is not maintained upon deletion of the repressor element. Instead, the number of cells in which the minigene is expressed increases from less than 1% to approximately 10% of the epithelial cells in the adult small intestine, and includes the majority of the goblet cells in addition to the enteroendocrine cells. In contrast, the pattern of AFP minigene expression in the enterocytes is unaffected by deletion of the repressor element and continues to decrease in the neonate. These studies indicate that the identified AFP repressor is active specifically in goblet cells. The decrease in AFP expression in the enterocytes may be mediated by a separate cis-acting element that is contained in the AFP minigene construct. Alternatively, it is possible that mature enterocytes lack some of the positive factors required for initiation and maintenance of minigene transcription in the absence of the identified negative element.

High-Throughput Screening for Modulators of CFTR Activity Based on Genetically Engineered Cystic Fibrosis Disease-Specific iPSCs

“…This might be prevented by addition of FGF4, which was shown to suppress the formation of hepatic gene expression at the hindgut stage (Tamminen et al., 2015). The hepatic and biliary markers detected, however, are also known to be expressed on intestinal cells during development (Cirillo et al., 1995, Stammberger and Baczako, 1999, Tsai et al., 2017, Verzi et al., 2013). Since on the other hand some marker genes for mature secretory epithelia cells (e.g., MUC2 , CHGA ) are not expressed in our intestinal cell population, we conclude that our intestinal cell population does not show a fully mature adult phenotype.…”

Regulation of Duodenal Specific Expression of the Human Adenosine Deaminase Gene

“…This intestinal regulatory segment from the ADA gene joins a growing list of intestine-specific elements from other genes (51)(52)(53)(54)(55)(56). Many of these genes have expression patterns that differ along the A/P and/or the C/V axis from each other.…”

Regulation and expression of multidrug resistance (MDR) transcripts in the intestinal epithelium

“…To our knowledge no promoter elements have been identified which function in developing or undifferentiated intestinal epithelial cells. To date, the regulation of only three genes which are expressed in undifferentiated intestine have been reported: the murine homeobox gene cdx-1 (Hu et al, 1993), the cystic fibrosis transmembrane conductance regulator (CFTR) (Koh et al, 1993;McDonald et al, 1995) and the fetal serum protein α-fetoprotein (AFP) (Tyner et al, 1990;Cirillo et al, 1995). In each of these cases, analysis was either performed in colonic carcinoma cell lines or focused on elements which repress expression in mature enterocytes.…”