TFF2/SP-deficient mice show decreased gastric proliferation, increased acid secretion, and increased susceptibility to NSAID injury
James J. Farrell, … , Daniel K. Podolsky, Timothy C. Wang
James J. Farrell, … , Daniel K. Podolsky, Timothy C. Wang
Published January 15, 2002
Citation Information: J Clin Invest. 2002;109(2):193-204. https://doi.org/10.1172/JCI12529.
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Article

TFF2/SP-deficient mice show decreased gastric proliferation, increased acid secretion, and increased susceptibility to NSAID injury

Abstract

Trefoil factor family 2 (TFF2), also known as spasmolytic polypeptide, is a member of the trefoil family of peptides and is expressed primarily in the mucous neck cells of the gastric mucosa. To study the physiologic role of TFF2, we have generated TFF2-deficient mice through targeted gene disruption. Homozygous mutant mice were viable and fertile without obvious gastrointestinal abnormalities. However, quantitative measurements revealed a significant decrease in gastric mucosal thickness and in gastric mucosal proliferation rates. In addition, there was a twofold increase in activated parietal cells resulting in a twofold increase in basal and stimulated gastric acid output and an undetectable serum gastrin level. The TFF2-deficient mice also showed a significant increase in the degree of gastric ulceration after administration of indomethacin. Taken together, these results suggest a physiologic role for TFF2 to promote mucosal healing through the stimulation of proliferation and downregulation of gastric acid secretion.

Authors

James J. Farrell, Douglas Taupin, Theodore J. Koh, Duan Chen, Chun-Mei Zhao, Daniel K. Podolsky, Timothy C. Wang

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Figure 1

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Targeted deletion of the mouse TFF2 gene. (a) Restriction map of the 15-...
Targeted deletion of the mouse TFF2 gene. (a) Restriction map of the 15-kb genomic clone mTFF2. The subcloned gene contained four coding exons, 3.5 kb of 5′ flanking sequence and 8 kb of 3′ flanking sequence. The mTFF2 gene spans 3,114 bases, encompassing four exons (depicted in numbered boxes) that span a total of 3.7 kb and introns of 879 bp, 772 bp, and 1,074 bp. Exon 1: bp 439 to 516; exon 2: bp 1,396 to 1,545; exon 3: bp 2,318 to 2,464; exon 4: bp 3,539 to 3,553. The peptide domains encoded are indicated by arrows. (b) Strategy for homologous recombination. A diagram of the TFF2-pPNT targeting vector (middle) designed to replace the BamH1–BamH1 fragment containing the TFF2 exons in the wild-type (top) with a PGK-neo cassette and a herpes simplex virus–thymidine kinase (HSV–thymidine kinase) cassette. The predicted mutant allele (bottom) generated by homologous recombination is also shown. The neomycin resistance gene (Neomycin) is retained in the mutant allele with homologous recombination, while the HSV–thymidine kinase is not. (c) Southern blot analysis of the homologous recombination. Southern blot analysis of wild–type (+/+), heterozygous (+/–), and TFF2-deficient (–/–) mice shows that the 6-kb Spe1 restriction fragment found in wild-type mice is lost in TFF2-deficient mice because of the deletion of a single Spe1 site just distal to exon 4, resulting in a 7.5-kb fragment. The 15-kb mTFF2 genomic clone in pBKS+ was used as a positive control (P). (d) Polymerase chain reaction analysis of tail DNA using the neomycin resistance gene and mouse TFF2 exon 2 primers reveals a solitary 0.6-kb fragment representing heterozygosity (+/–) and a solitary 0.15-kb fragment representing wild-type (+/+).