Production and Characterization of <i>Reg</i> Knockout Mice

Unno, Michiaki; Nata, Koji; Noguchi, Naoya; Narushima, Yoichi; Akiyama, Takako; Ikeda, Takayuki; Nakagawa, Kazuhiko; Takasawa, Shin; Okamoto, Hiroshi

doi:10.2337/diabetes.51.2007.s478

Cited by 103 publications

(102 citation statements)

References 33 publications

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“…Although Reg proteins are known to function as ␤ cell trophic factors, it has also been shown that Reg2 in the pancreas can function as an autoantigen and the target of an islet-destructive process (28,29). However, when Reg was specifically expressed as a transgene in the pancreas of NOD mice, the onset of diabetes was significantly delayed (23). Although the molecular mechanism leading to up-regulated Reg expression in the Il21r-KO remains to be determined, it is thus possible that the augmented Reg gene expression contributes to the protective effect from diabetes observed in the Il21r-KO NOD mice.…”

Section: Discussionmentioning

confidence: 96%

“…Regenerating gene (Reg) was identified as a gene that is upregulated in regenerating pancreatic ␤ islet cells (22). Whereas deletion of the Reg2 gene led to decreased proliferation of the pancreatic ␤ islet cells, NOD mice carrying a Reg2 transgene specifically expressed in the pancreas displayed a significant delay in the onset of diabetes (23). We therefore examined the expression of two members of this family of proteins, Reg2 and PAP, in the pancreas of WT and Il21r-KO mice either on the NOD or on the C57BL/6 background.…”

Section: Normal T Cell Populations and Cytokine Production In Nod/il2mentioning

confidence: 99%

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IL-21 signaling is critical for the development of type I diabetes in the NOD mouse

Spolski

Kashyap

Robinson

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

188

161

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IL-21 is a pleiotropic type I cytokine that shares the common cytokine receptor ␥ chain and plays important roles for normal Ig production, terminal B cell differentiation to plasma cells, and Th17 differentiation. IL-21 is elevated in several autoimmune diseases, and blocking its action has attenuated disease in MRL/lpr mice and in collagen-induced arthritis. The diabetes-associated Idd3 locus is at the Il2/Il21 locus, and elevated IL-21 was observed in the nonobese diabetic (NOD) mouse and suggested to contribute to diabetes by augmenting T cell homeostatic proliferation. To determine the role of IL-21 in diabetes, Il21r-knockout (KO) mice were backcrossed to NOD mice. These mice were devoid of lymphocytic infiltration into the pancreas, and only 1 of 20 animals had an elevated glucose compared with 60% of NOD mice on a wild-type (WT) background. Although TCR and Treg-related responses were normal, these mice had reduced Th17 cells and significantly higher levels of mRNAs encoding members of the Reg (regenerating) gene family whose transgenic expression protects against diabetes. Our studies establish a critical role for IL-21 in the development of type I diabetes in the NOD mouse, with obvious potential implications for type I diabetes in humans. Reg genes ͉ Th17 cellsH uman type I diabetes is an autoimmune disease that results from the autoreactive destruction of pancreatic ␤ cells and subsequent loss of insulin production (1). Nonobese diabetic (NOD) mice develop a similar disease and serve as a model system for studying the mechanisms involved in the initiation and propagation of the autoimmune response (2). Although it has been established that ␤ islet cell destruction is initiated by proinflammatory CD4 ϩ and CD8 ϩ T cells infiltrating the pancreas, the molecular mechanisms and cytokine pathways that control this process are not fully understood.IL-21 is a type I cytokine (3) that is the most recently discovered member of the family of cytokines that share the common cytokine receptor ␥ chain, ␥ c (4) . ␥ c is also shared by IL-2, IL-4, IL-7, IL-9, and IL-15 and is mutated in humans with X-linked severe combined immunodeficiency (XSCID) (5). IL-21 is produced most abundantly by CD4 ϩ T cells, including Th17 lineage cells (6-8) and natural killer T (NKT) cells (9), and is known to act on both lymphoid and nonlymphoid target cells, thus controlling both innate and adaptive immune responses (4). IL-21 is critical for normal Ig production (10), can cooperatively drive expansion of CD8 ϩ T cells (11), can activate NK cells (12), and drives terminal B cell differentiation into plasma cells (13). IL-21 has been implicated as playing a role in the development of B cell-mediated lupus-like autoimmune disease based on studies in the BXSB-Yaa (13), Sanroque (14), and MRL/lpr mice (15), and treatment with a soluble IL-21R-Fc fusion protein was shown to lead to a partial decrease in disease severity in the MRL/lpr mice (15) and collagen-induced arthritis (16). In experimental allergic encephalitis (EAE), a model for ...

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Section: Discussionmentioning

confidence: 96%

Section: Normal T Cell Populations and Cytokine Production In Nod/il2mentioning

confidence: 99%

IL-21 signaling is critical for the development of type I diabetes in the NOD mouse

Spolski

Kashyap

Robinson

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

188

161

View full text Add to dashboard Cite

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“…Generation of the Reg I-knockout mice is described in our previous report (Unno et al, 2002). Reg I-knockout mice (Reg À/À ) were bred with ICR wild-type mice (Nihon Clea, Tokyo, Japan), generating Reg þ /À mice.…”

Section: Animalsmentioning

confidence: 99%

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

et al. 2006

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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.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Jing

Kehoe

Tzanakakis

2010

Stem Cells and Development

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Regenerating islet (Reg) proteins are involved in the proliferation and differentiation of diverse cell types. However, whether embryonic stem cells (ESCs) express Reg genes and their corresponding proteins remains unknown. In this study, we probed the expression of Reg family members by mouse ESCs (mESCs). Mouse Reg1 and Reg3γ were detected in undifferentiated stem cells. Furthermore, we tested if gastrin-an inducer of Reg1 expression in committed cells-up-regulates the Reg1 gene in mESCs. Gastrin did not affect the expression of Reg1 either in self-renewing mESCs or under conditions permitting their differentiation. Moreover, overexpression of Reg genes found in various forms of cancer has been linked to dysregulated activation of the canonical Wnt/β-catenin cascade. Given the important roles of Wnt signaling in stem cells, we investigated if activation of Wnt alters the expression of Reg genes in mESCs. Wnt activation led to an increase in Reg1 gene expression with a concomitant increase in the amount of secreted Reg1 protein. Finally, the expression pattern of genes indicative of differentiation was examined in mESCs that were either exposed to soluble Reg1 or overexpressed the Reg1 gene. This is the fi rst account of expression of Reg family members by ESCs. Our results show that the canonical Wnt cascade affects Reg expression and warrants further studies into the potential roles of Reg proteins in stem cell physiology.

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Production and Characterization of Reg Knockout Mice

Cited by 103 publications

References 33 publications

IL-21 signaling is critical for the development of type I diabetes in the NOD mouse

IL-21 signaling is critical for the development of type I diabetes in the NOD mouse

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

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

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