Brain expression of Cre recombinase driven by pancreas‐specific promoters

Song, Jia; Xu, Yuanzhong; Hu, Xiaoxia; Choi, Brian; Tong, Qingchun

doi:10.1002/dvg.20672

Cited by 97 publications

(99 citation statements)

References 39 publications

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“…The transgenic expression in RIP-I/Reg3␤ mice was specific, as other tissues (duodenum, cerebellum, hypothalamus, liver, and muscle) did not show increased Reg3␤ mRNA level using real-time PCR vs. wild-type counterparts (data not shown). This was in agreement with the findings that insulin I gene was specifically expressed in the ␤-cells, unlike the insulin II promoter that directed a significant, ectopic expression in the brain (33,49,58).…”

Section: Resultssupporting

confidence: 81%

“…A recent evaluation of several strains expressing Cre recombinase and directing conditional gene targeting revealed that the commonly used rat insulin II promoter (668 bp, often marked as RIP) caused ectopic recombination in most brain areas, especially the midbrain and ventral regions, in addition to the islet ␤-cells (11,49,58); Pdx1-Cre also caused an unexpected recombination in a subset of hypothalamic neurons involved in energy and nutrient homeostasis (58). On the other hand, an 8.5-kb mouse insulin I promoter was successfully used to express cGFP and Cre exclusively in the ␤-cells (58).…”

Section: Discussionmentioning

confidence: 99%

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Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus

Xiong

Wang

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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. Pancreatic islet-specific overexpression of Reg3␤ protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus. Am J Physiol Endocrinol Metab 300: E669 -E680, 2011. First published January 18, 2011; doi:10.1152/ajpendo.00600.2010.-Reg family proteins have been implicated in islet ␤-cell proliferation, survival, and regeneration. The expression of Reg3␤ (pancreatitis-associated protein) is highly induced in experimental diabetes and acute pancreatitis, but its precise role has not been established. Through knockout studies, this protein was shown to be mitogenic, antiapoptotic, and anti-inflammatory in the liver and pancreatic acinars. To test whether it can promote islet cell growth or survival against experimental damage, we developed ␤-cell-specific overexpression using rat insulin I promoter, evaluated the changes in normal islet function, gene expression profile, and the response to streptozotocin-induced diabetes. Significant and specific overexpression of Reg3␤ was achieved in the pancreatic islets of RIP-I/Reg3␤ mice, which exhibited normal islet histology, ␤-cell mass, and in vivo and in vitro insulin secretion in response to high glucose yet were slightly hyperglycemic and low in islet GLUT2 level. Upon streptozotocin treatment, in contrast to wild-type littermates that became hyperglycemic in 3 days and lost 15% of their weight, RIP-I/Reg3␤ mice were significantly protected from hyperglycemia and weight loss. To identify specific targets affected by Reg3␤ overexpression, a whole genome DNA microarray on islet RNA isolated from the transgenic mice revealed more than 45 genes significantly either up-or downregulated. Among them, isletprotective osteopontin/SPP1 and acute responsive nuclear protein p8/NUPR1 were significantly induced, a result further confirmed by real-time PCR, Western blots, and immunohistochemistry. Our results suggest that Reg3␤ is unlikely an islet growth factor but a putative protector that prevents streptozotocin-induced damage by inducing the expression of specific genes.pancreatitis-associated protein; DNA microarray; real-time polymerase chain reaction; Western blot; immunofluorescence; Reg family proteins; transgenic mice A NORMAL ␤-CELL MASS is a crucial element against the development of diabetes mellitus and is determined by at least four independent parameters, i.e., mitogenic replication, cell size expansion, neogenesis (from other pancreatic cells), and apoptosis (42). The net rate of ␤-cell growth is the balance among the rates of ␤-cell replication, hypertrophy, neogenesis, and apoptosis (10). Various growth factors such as hepatocyte growth factor and glucagon-like peptide-1 (GLP-1) have been reported to stimulate islet cell expansion (12, 13, 43). For a therapeutic purpose, ␤-cell mass could also be supplemented by islet cell transplantation where growth factors were shown to promote the survival and/or expansion of transplanted cells in rodents (8,43). Unfortunately, very few of these factors have been pr...

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Section: Resultssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus

Xiong

Wang

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…1B). Because Pdx1-Cre is active in the hypothalamus (36,46,47), a region of the central nervous system critical for metabolic control, we analyzed Foxd3 mRNA expression in the hypothalamus of control animals using RT-PCR and determined that Foxd3 mRNA was not detectable in this region (Supplemental Fig. 1, published Fig.…”

Section: Figmentioning

confidence: 99%

Loss of Foxd3 Results in Decreased β-Cell Proliferation and Glucose Intolerance During Pregnancy

et al. 2011

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A complete molecular understanding of ␤-cell mass expansion will be useful for the improvement of therapies to treat diabetic patients. During normal periods of metabolic challenges, such as pregnancy, ␤-cells proliferate, or self-renew, to meet the new physiological demands. The transcription factor Forkhead box D3 (Foxd3) is required for maintenance and self-renewal of several diverse progenitor cell lineages, and Foxd3 is expressed in the pancreatic primordium beginning at 10.5 d postcoitum, becoming localized predominantly to ␤-cells after birth. Here, we show that mice carrying a pancreas-specific deletion of Foxd3 have impaired glucose tolerance, decreased ␤-cell mass, decreased ␤-cell proliferation, and decreased ␤-cell size during pregnancy. In addition, several genes known to regulate proliferation, Foxm1, Skp2, Ezh2, Akt2, and Cdkn1a, are misregulated in islets isolated from these Foxd3 mutant mice. Together, these data place A pproximately 7% of pregnant women are affected by gestational diabetes mellitus (GDM), a disease resulting from the inability of the resident ␤-cell population to produce sufficient insulin during pregnancy (1). GDM increases the risk of complications to both mother and newborn child; the mother is more likely to develop type 2 diabetes later in life, and the child is more likely to be born with birth defects, macrosomia, and an increased risk of developing type 2 diabetes (2-6). During normal murine pregnancy, ␤-cells proliferate, or self-renew, thereby expanding the total ␤-cell mass to meet the mother's increasing demand for insulin (1,(7)(8)(9)(10)(11)(12). This mechanism of ␤-cell mass expansion during human pregnancy remains controversial. Analogous measurements are not ethically feasible in humans. However, morphological analyses of human pancreata indicate that ␤-cell mass is increased during pregnancy (13,14). Recent work analyzing pancreata from 38 cadaveric donors (18 pregnant, 20 controls) suggested that ␤-cells do not proliferate during human pregnancy. Instead, an increased number of smaller islets and insulin-positive cells was observed within the ductal epithelium (15). However, this work is not without caveats. It is well known that murine ␤-cells proliferate within a defined time window, and it is likely that the 18 pregnant human donors examined were not within an analogous gestational age (16,17). This study also included donors with inflammatory disease that may have adversely affected ␤-cell mass expansion (18). It is important to note that the pregnancy-associated hormones prolactin, placental lactogen (PL), and human growth hormone all stimulate ␤-cell proliferation in islets isolated from mice, rats, and humans, suggesting that cell proliferation is a conserved mechanism of Abbreviations: BrdU, 5-Bromo-2-deoxyuridine; Cdkn, cyclin-dependent kinase inhibitor; ES, embryonic stem; Ezh2, enhancer of zeste homolog 2; Foxa2, Forkhead box A2; Foxd3, Forkhead box D3; Foxm1, forkhead box M1; GDM, gestational diabetes mellitus; IPGTT, ip glucose tolerance testing;...

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“…However, Oropeza et al (12) provide a more extensive and detailed analysis of this mouse model. First, strong evidence is provided using higher resolution techniques and the mT/mG reporter line (20) that Cre activity is indeed exclusively found in b-cells and not in hypothalamic or hindbrain nuclei, as was reported before in other strains (7,8). Furthermore, whole-body glucose homeostasis was similar to controls, both on normal chow and after a high-fat, high-sucrose (HFHS) diet.…”

mentioning

confidence: 52%

“…There have been reports of disturbed endogenous gene expression at the site of the Cre-transgene insertion (4), low or mosaic Cre expression (5,6), and expression in undesired tissues, such as unwanted Cre activity in nutrient-sensing neurons from transgenic mice that express Cre under the control of Ins2 and Pdx1 promoters (7,8). Equally disturbing is the finding that high Cre activity can cause chromosomal rearrangements, apoptosis, and decreased proliferation (9-11).…”

mentioning

confidence: 99%