Reg I-knockout mice reveal its role in regulation of cell growth that is required in generation and maintenance of the villous structure of small intestine

Abstract

Reg I (regenerating gene product I) is a growth factor that plays a central role in the generation and regeneration of the gastric mucosal architecture. On the other hand, mouse Reg I mRNA is expressed at the highest levels in the small intestine among the gastrointestinal tissues. In the current study, with the aim to clarify the role of Reg I protein in the small intestine, the temporal and spatial pattern of Reg I expression and the phenotype of Reg I-knockout mice in the tissue were examined. In the wild-type mice, immunohistochemistry localized Reg I protein expression in absorptive cells located in the lower half of the intestinal villi. Reg I expression was undetectable until embryonic day 13 (E13), when the fetal intestine still lacks villous structure; however, it dramatically increased at E17 along with the formation and maturation of the fetal intestinal villi. In the small intestine of the adult Reg I-knockout mice, less densely packed, round-shaped aberrant morphology of the absorptive cells was observed light microscopically, and electron microscopical examination revealed a strikingly loose connection of these cells to the basement membrane. Antiproliferating cell nuclear antigen staining and anti-Ki67 staining demonstrated the marked decrease in the number of proliferating cells in the small intestinal mucosa of the knockout mice. The cell migration speed visualized by one shot labeling of 5-bromodeoxyuridine was significantly slower in the knockout mice. These phenotypes of Reg I-knockout mice emerged, in accordance with the temporal pattern of Reg I expression described above, from E17. Reg I was considered to be a regulator of cell growth that is required to generate and maintain the villous structure of the small intestine.

Involvement of the IL-22/REG Iα axis in ulcerative colitis

“…Conversely, along with others, we have suggested that REG family proteins are importantly involved in the regeneration of gastrointestinal mucosa by exerting mitogenic and/or antiapoptotic effects. 4,6,27,41 Accordingly, together with our present data, it is tempting to speculate that REG family proteins are pivotal targets for IL-22 in protecting the colonic mucosa from inflammation-associated injury, although further studies will be needed to test this hypothesis.…”

Expression of Reg Family Proteins in Embryonic Stem Cells and Its Modulation by Wnt/β-Catenin Signaling

“…Regenerating islet (Reg) proteins have been identifi ed in various types of regenerating tissues [10,11,51,52] and cancer cells [ 13,14,16 ] and the expression patterns of Reg genes have been under intense scrutiny. To date, however, there clearly demonstrate an increase in Reg1 expression in mouse MIN6 insulinoma β-cells treated with gastrin.…”

“…The Reg2 protein is a potent mitogen of Schwann cells and contributes to the regeneration of motor neurons in mice [ 10 ]. Moreover, the generation and maintenance of the villous structure of the small intestine is infl uenced by Reg1, which is considered a regulator of intestinal cell growth [ 11 ]. Despite the intimate link between Reg proteins and the proliferation and/or differentiation of diverse types of cells, no information is available, to date, about the expression and regulation of members of the Reg family in embryonic stem cells (ESCs).…”

In vivo evidence for the role of RegI in gastric regeneration: transgenic overexpression of RegI accelerates the healing of experimental gastric ulcers

“…9 The following primary antibodies were used in this study: monoclonal mouse IgG2a anti-mouse proliferating cell nuclear antigen (Santa Cruz Biotechnology) (1:1000) and monoclonal mouse IgG2a anti-rat RegI antibody (1:50). 11 For double staining of Tg RegI protein and chromogranin A, the tissue slides were first stained for RegI as described above.…”

“…8 Previous reports 9,10 showed that the mouse stomach, in contrast to the rat stomach, shows very low levels of RegI expression, providing an ideal experimental system with which to test the effects of the regI transgene. Tg mice of 3 weeks old, just finishing the period of gastric gland morphogenesis, showed apparent gastric mucosal hypertrophy and elevated expression of a cell proliferation marker, compared with littermate controls.…”