Contribution of gastrin-releasing peptide and its receptor to villus development in the murine and human gastrointestinal tract

• Published in: Mechanisms of development 2002-05, Vol.113 (2), p.121-130
• Main Authors: Carroll, Robert E, Matkowskyj, Kristina, Saunthararajah, Yogen, Sekosan, Marin, Battey, James F, Benya, Richard V
• Format: Article
• Language: English
• Subjects: Aborted Fetus; Animals; Cell Division; Cell Separation; Digestive System - embryology; Enterocytes - metabolism; Flow Cytometry; Gastrin-Releasing Peptide - biosynthesis; Gastrin-Releasing Peptide - physiology; Genotype; Humans; Immunohistochemistry; Mice; Phenotype; Receptors, Bombesin - biosynthesis; Receptors, Bombesin - physiology; Time Factors
• ISSN: 0925-4773; 1872-6356
• DOI: 10.1016/S0925-4773(02)00032-1

Recent studies have shown that aberrantly expressed gastrin-releasing peptide (GRP) and its receptor (GRP-R) critically regulate tumor cell differentiation in colon cancers developing in humans and mice. This finding suggested that the ability of GRP/GRP-R to promote a well-differentiated phenotype in colon cancer might reflect a re-capitulation of a normal role in regulating intestinal organogenesis. To determine if this was the case, we compared and contrasted intestinal development in GRPR −/− mice with their wild type littermates. GRP/GRP-R co-expression in wild type mice was only observed in villous enterocytes between N-1 and N-12. During this time frame villous growth was completely attenuated in GRPR −/− mice. The contribution of GRP/GRP-R to villous growth was due to their act in increasing enterocyte proliferation prior to N-8 but increasing enterocyte size thereafter. From N-12 onwards, small intestinal villous growth in GRPR −/− mice resumed such that no difference in this structure could be detected at adulthood between mice of either genotype. We next studied GRP/GRP-R expression in human abortuses. These proteins were co-expressed by villous enterocytes only between weeks 14 and 20 post-conception, a time frame analogous to when they are expressed in the murine intestine. Thus, this study shows for the first time that GRP/GRP-R play a transient and non-critical role in intestinal development, yet provides a rationale for their re-appearance in colon cancer.