Analysis Tools|
Allele Symbol Allele Name Allele ID |
Tg(Pdx1-cre)89.1Dam transgene insertion 89.1, Douglas A Melton MGI:2684317 |
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| Summary |
56 genotypes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• numbers of mutant offspring identified at weaning (15.3%) are significantly lower than expected Mendelian numbers (25%)
• expected numbers of double mutant offspring are present embryonically and at birth, but many die by P5
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• 2-4 month old mice show decreased insulin secretion
• islets show diminished insulin responsiveness to glucose, KCL, exendin 4, forskolin and 8-bromo-cAMP, indicating a block in exocytosis
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• 2-4 month old mice show increased ad libitum glucose levels throughout the day
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• 2-4 month old mice show impaired glucose tolerance
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• beta-cell function is defective at the very latest stage of stimulus-secretion coupling
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• 2-4 month old mice show decreased insulin secretion
• islets show diminished insulin responsiveness to glucose, KCL, exendin 4, forskolin and 8-bromo-cAMP, indicating a block in exocytosis
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| N |
• mice show normal circadian activity, feeding rhythms and body weight
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| diabetes mellitus | DOID:9351 | J:162641 | ||
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice with cerulein-induced acute pancreatitis show reversion of acinar-ductal metaplasia lesions to normal acinar morphology after 7 days of recovery as in wild-type mice
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• primary pancreatic acinar cells from 1.5-month-old mice grown in 3D collagen culture show attenuated KRAStm4Tyj-induced acinar cell transdifferentiation and acinar-ductal metaplasia formation
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• primary pancreatic acinar cells from 1.5-month-old mice grown in 3D collagen culture show attenuated KRAStm4Tyj-induced acinar cell transdifferentiation and acinar-ductal metaplasia formation
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice develop pancreatic cancer
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• all pancreata of 7-month old mice are replaced by aggressive pancreatic ductal adenocarcinoma with lung and liver metastasis
• circulating pancreatic neoplastic cells are increased in the blood of mice harboring pancreatic adenocarcinoma
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• 100% of 3-month old mice exhibit abundant acinar-ductal metaplasia and low- and high-grade pancreatic intraepithelial neoplasia (PanIN) lesions
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• average survival is 5.2 +/- 1.2 months
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• mice develop pancreatic cancer
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• all pancreata of 7-month old mice are replaced by aggressive pancreatic ductal adenocarcinoma with lung and liver metastasis
• circulating pancreatic neoplastic cells are increased in the blood of mice harboring pancreatic adenocarcinoma
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• 100% of 3-month old mice exhibit abundant acinar-ductal metaplasia and low- and high-grade pancreatic intraepithelial neoplasia (PanIN) lesions
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• 100% of 3-month old mice exhibit abundant acinar-ductal metaplasia and low- and high-grade pancreatic intraepithelial neoplasia (PanIN) lesions
• circulating pancreatic neoplastic cells are increased in the blood of mice harboring PanI
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|
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice with cerulein-induced acute pancreatitis show reversion of acinar-ductal metaplasia lesions to normal acinar morphology after 7 days of recovery similarly as in wild-type mice
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|
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• 73.3% of 3-month old and 75% of 12-month old mice show normal pancreas
• although 26.7% of 3-month old and 25% of 12-month old mice show rare acinar-ductal metaplasia and low-grade pancreatic intraepithelial neoplasia (PanIN1) lesions, these lesions express TRIM29 due to incomplete recombination of the floxed allele
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| N |
• all mice are alive at 12 months
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• primary pancreatic acinar cells from 1.5-month-old mice grown in 3D collagen culture undergo acinar-ductal metaplasia, forming large duct-like structures, indicating induction of acinar-to-ductal transdifferentiation
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• mice with cerulein-induced acute pancreatitis do not show reversion of acinar-ductal metaplasia lesions to normal acinar morphology as in wild-type mice and show complete replacement of pancreatic tissue with fibrosis, infiltration of inflammatory cells, widespread acinar-ductal metaplasia/ pancreatic intraepithelial neoplasia (PanIN) lesions with loss of amylase-expressing acinar tissue, and maintain a small and persistent fraction of apoptotic cells
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• mice with cerulein-induced acute pancreatitis do not show reversion of acinar-ductal metaplasia lesions to normal acinar morphology as in wild-type mice and show complete replacement of pancreatic tissue with fibrosis, infiltration of inflammatory cells, widespread acinar-ductal metaplasia/ pancreatic intraepithelial neoplasia (PanIN) lesions with loss of amylase-expressing acinar tissue, and maintain a small and persistent fraction of apoptotic cells
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• islet cells isolated from 12 week old males secrete a third less insulin in response to high glucose as compared to wild-type controls
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• 30 minutes after glucose injection, mice only had a 30% rise in insulin compared to a 100% rise in wild-type mice
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• Mafb production in cells producing more than one hormone suggests delayed maturity of the secretory cells of the pancreas
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• 10% of pancreatic polypeptide producing cells also express somatostatin which represents a 5 fold increase compared to wild-type controls
• 4.1% of pancreatic polypeptide producing cells also express insulin which represents a 20 fold increase compared to wild-type controls
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• 2.7% of glucogon producing cells also produce insulin representing a 10 fold increase over wild-type controls
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• islet cells isolated from 12 week old males secrete a third less insulin in response to high glucose as compared to wild-type controls
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mutants develop pancreatic tumors with an average latency of 6.5 weeks
• 20% of tumors exhibit anaplastic carcinoma histology
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• 80% of tumors exhibit well differentiated ductal adenocarcinoma histology
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• mutants develop pancreatic tumors with an average latency of 6.5 weeks
• 20% of tumors exhibit anaplastic carcinoma histology
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• 80% of tumors exhibit well differentiated ductal adenocarcinoma histology
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| pancreatic ductal adenocarcinoma | DOID:3498 | J:108298 | ||
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mutants develop pancreatic tumors with an average latency of 18.3 weeks
• 100% of tumors are sarcomatoid in histology
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• 33% of tumors exhibit metastasis
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• mutants develop pancreatic tumors with an average latency of 18.3 weeks
• 100% of tumors are sarcomatoid in histology
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mutants develop pancreatic tumors with an average latency of 13.1 weeks
• 25% of tumors exhibit sarcomatoid carcinoma histology
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• 75% of tumors exhibit well differentiated ductal adenocarcinoma histology
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• 25% of tumors exhibit metastasis
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• mutants develop pancreatic tumors with an average latency of 13.1 weeks
• 25% of tumors exhibit sarcomatoid carcinoma histology
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• 75% of tumors exhibit well differentiated ductal adenocarcinoma histology
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| pancreatic ductal adenocarcinoma | DOID:3498 | J:108298 | ||
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mutants develop pancreatic tumors with an average latency of 14.7 weeks
• 19% of tumors exhibit sarcomatoid differentiation
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• 81% of tumors exhibit well differentiated ductal adenocarcinoma histology
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• 25% of tumors exhibit metastasis
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• mutants develop pancreatic tumors with an average latency of 14.7 weeks
• 19% of tumors exhibit sarcomatoid differentiation
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• 81% of tumors exhibit well differentiated ductal adenocarcinoma histology
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mutants develop pancreatic tumors with an average latency of 21.8 weeks
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• 100% of tumors are well differentiated ductal adenocarcinomas
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• 33% of tumors exhibit metastasis
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• mutants develop pancreatic tumors with an average latency of 21.8 weeks
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• 100% of tumors are well differentiated ductal adenocarcinomas
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mutants develop pancreatic tumors with an average latency of 7.2 weeks
• 60% of tumors exhibit anaplastic carcinoma histology
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• 40% of tumors exhibit well differentiated ductal adenocarcinoma histology
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• 20% of tumors exhibit metastasis
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• mutants develop pancreatic tumors with an average latency of 7.2 weeks
• 60% of tumors exhibit anaplastic carcinoma histology
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• 40% of tumors exhibit well differentiated ductal adenocarcinoma histology
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| pancreatic ductal adenocarcinoma | DOID:3498 | J:108298 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants develop pancreatic tumors with an average latency of 6.2 weeks
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• mutants exhibit rapid pancreatic ductal adenocaracinoma progression, developing lethal tumors by 8 weeks of age
• 100% of tumors are well differentiated ductal adenocarcinomas
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• mutants develop pancreatic tumors with an average latency of 6.2 weeks
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• mutants exhibit rapid pancreatic ductal adenocaracinoma progression, developing lethal tumors by 8 weeks of age
• 100% of tumors are well differentiated ductal adenocarcinomas
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| pancreatic ductal adenocarcinoma | DOID:3498 | J:108298 | ||
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
 |
• islets from pregnant mutants do not exhibit an increase in insulin content as seen in pregnant wild-type females
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• pregnant females show decreased beta cell mass at gestational day 19 compared to controls, at a time when maximal beta-cell mass expansion occurs during pregnancy
• the decrease in beta-cell mass persists at postpartum day 4
• however, islet number and beta-cell size are similar to wild-type at gestational day 19
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• apoptosis in beta-cells of mutant pregnant females is premature and is increased at gestational day 15, however at gestational day 19 and postpartum day 4, beta cell apoptosis is increased similarly in wild-type and mutant pregnant females
• mutant beta cells are more sensitive to the cytotoxic effects of a low dose of the synthetic hormone dexamethasone that does not induce cell death in wild-type islets
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• pregnant females show a decrease in beta-cell proliferation at gestational day 15, when maximal beta-cell proliferation normally occurs during pregnancy
• beta-cell proliferation is also decreased at postpartum day 4
• however, beta-cell proliferation is similar to wild-type at gestational day 11 and 19
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• islets from pregnant mutants do not exhibit an increase in insulin content as seen in pregnant wild-type females
• islets from mutant pregnant females do not exhibit an increase in glucose-stimulated insulin secretion at gestational day 19 that is seen in wild-type pregnant females
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• islets from pregnant mutants do not exhibit an increase in insulin content as seen in pregnant wild-type females
• islets from mutant pregnant females do not exhibit an increase in glucose-stimulated insulin secretion at gestational day 19 that is seen in wild-type pregnant females
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• blood glucose is higher in pregnant mutant females at gestational day 19 than in wild-type pregnant females
• fasting blood glucose is increased in pregnant mutant females at gestational day 19 than in wild-type pregnant females
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• plasma insulin levels are diminished in pregnant mutant females at gestational day 19 compared to wild-type pregnant females
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• glucose tolerance is impaired more in pregnant mutant females than pregnant wild-type females at gestational day 15 and 19 and at postpartum day 4
• pregnant mutant females respond similarly to insulin tolerance tests at gestational day 18 as wild-type females, indicating that enhanced impairment in glucose tolerance is not related to changes in insulin sensitivity
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• pregnant females show a decrease in beta-cell proliferation at gestational day 15, when maximal beta-cell proliferation normally occurs during pregnancy
• beta-cell proliferation is also decreased at postpartum day 4
• however, beta-cell proliferation is similar to wild-type at gestational day 11 and 19
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| gestational diabetes | DOID:11714 | J:196854 | ||
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice fed standard chow exhibit normal blood glucose levels, glucose tolerance and insulin sensitivity
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• stimulated by glucose in mice fed a high fat diet
• reduced pancreatic insulin content in mice fed a high fat diet treated with STZ
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• in mice treated with STZ
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• in mice treated with STZ
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• in mice fed a high fat diet
• however, mice fed standard chow exhibit normal glucose tolerance
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• in mice fed a high fat diet
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• decreased individual islet size and total islet area in mice fed a high fat diet
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• increased beta cell apoptosis in mice fed a high fat diet
• beta cells exhibit increased sensitivity to cytokine-induced cell death compared with wild-type cells
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• in mice fed a high fat diet
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• stimulated by glucose in mice fed a high fat diet
• reduced pancreatic insulin content in mice fed a high fat diet treated with STZ
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• in mice fed a high fat diet
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• 1 of 5 mutants develop a small acinar carcinoma
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• 2 of 5 mutants develop papillary adenocarcionomas at 4 and 6 months of age
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• 1 of 5 mutants develop a small acinar carcinoma
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• 2 of 5 mutants develop papillary adenocarcionomas at 4 and 6 months of age
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Pancreatic tumors in Krastm4Tyj/Krastm4Tyj Trim33tm1Los/Trim33tm1Los Tg(Pdx1-cre)89.1Dam/0 and Krastm4Tyj/Krastm4Tyj Cdkn2atm4Rdp/Cdkn2atm4Rdp Tg(Pdx1-cre)89.1Dam/0 mice
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• over time endocrine and exocrine components are replaced with abnormal ductal structures
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• as early as 3 weeks, mice develop enlarged and dilated ductal structures resembling budding cysts unlike in wild-type mice
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• with age, islets become disorganized
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• as early 7 weeks
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• mice develop pancreatic intraepithelial neoplasia and tumors reminiscent of human intraductal papillary mucinous neoplasm
• however, mice do not exhibit macroscopic evidence of invasive carcinoma
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• as early as 3 weeks, mice develop pancreatic intraepithelial neoplasias
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• as early 7 weeks, mice exhibit multifocal cystic lesions unlike wild-type mice
• all mice develop cysts that at 6 weeks occupy 50% of the pancreatic area unlike in wild-type mice
• cysts are composed of epithelial cells with cuboidal or cylindrical morphologies that form numerous papillary projections into the cysts
• papillary projections contain masses of small monomorphic cells with an endocrine morphology
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• as early as 3 weeks, mice develop acute inflammation of the pancreas unlike wild-type mice
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• mice develop pancreatic intraepithelial neoplasia and tumors reminiscent of human intraductal papillary mucinous neoplasm
• however, mice do not exhibit macroscopic evidence of invasive carcinoma
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• as early as 3 weeks, mice develop pancreatic intraepithelial neoplasias
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• as early as 3 weeks, mice develop acute inflammation of the pancreas unlike wild-type mice
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• as early as 3 weeks, mice develop enlarged and dilated ductal structures resembling budding cysts unlike in wild-type mice
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• as early 7 weeks
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• as early 7 weeks, mice exhibit multifocal cystic lesions unlike wild-type mice
• all mice develop cysts that at 6 weeks occupy 50% of the pancreatic area unlike in wild-type mice
• cysts are composed of epithelial cells with cuboidal or cylindrical morphologies that form numerous papillary projections into the cysts
• papillary projections contain masses of small monomorphic cells with an endocrine morphology
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• pancreatic development is normal
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|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants exhibit accelerated development of acinar-to-ductal metaplasia, malignant pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma compared to single heterozygous Kras mutants, with almost 100% of mutants succumbing to cancer by 12 months of age
• 21 of 25 mice alive past 2 months of age develop well-to-moderately differentiated invasive ductal cancers
• rare metastasis to lungs is seen
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• at 3 months of age, 8 of 12 mutants show development of pancreatic ductal adenocarcinoma (PDAC), and all mice show PDAC by 6 months of age
• loss of Pten heterozygosity is seen during pancreatic ductal adenocarcinoma progression but not in mPanIN lesions
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• mutants show malignant pancreatic intraepithelial neoplasia (mPanIN) development starting at 1 month of age, and all show mPanIN by 3 months of age
|
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• median survival time is about 3.5 months
|
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• mutants exhibit accelerated development of acinar-to-ductal metaplasia, malignant pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma compared to single heterozygous Kras mutants, with almost 100% of mutants succumbing to cancer by 12 months of age
• 21 of 25 mice alive past 2 months of age develop well-to-moderately differentiated invasive ductal cancers
• rare metastasis to lungs is seen
|
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• at 3 months of age, 8 of 12 mutants show development of pancreatic ductal adenocarcinoma (PDAC), and all mice show PDAC by 6 months of age
• loss of Pten heterozygosity is seen during pancreatic ductal adenocarcinoma progression but not in mPanIN lesions
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• mutants show malignant pancreatic intraepithelial neoplasia (mPanIN) development starting at 1 month of age, and all show mPanIN by 3 months of age
|
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• acinar-to-ductal metaplasia is seen at 1-3 months of age, concentrated in the transition zone between morphologically normal pancreatic structures and mPanIN and PDAC lesions
• acinar-to-ductal metaplasia development precedes mPanIN formation
• metaplastic lesions show an increase in CD44+ cells
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| pancreatic carcinoma | DOID:4905 |
OMIM:260350 |
J:164210 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• all mutants develop pancreatic ductal adenocarcinoma by 3 weeks of age
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• mutants show severe exocrine pancreatic atrophy and edema along with the presence of mPanINs, metaplasias, and ducto-insular complexes and pancreatic ductal adenocarcinoma at P17
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• severe
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• all mutants develop pancreatic ductal adenocarcinoma by 3 weeks of age
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• mutants exhibit acinar-to-ductal metaplasia
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• mutants are moribound by weaning, with a median survival of about 17 days
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• mutants show severe exocrine pancreatic atrophy and edema along with the presence of mPanINs, metaplasias, and ducto-insular complexes and pancreatic ductal adenocarcinoma at P17
|
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• severe
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| pancreatic carcinoma | DOID:4905 |
OMIM:260350 |
J:164210 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• average cancer free survival is greater than 52 weeks and 2 of 9 mice develop pancreatic ductal adenocarcinoma
(J:116130)
• 2 of 11 mutants show evidence of pancreatic ductal adenocarcinoma at 6 months of age, but not at earlier times
(J:164210)
|
|
• pancreatic ductal lesions are seen at 9, 12, 18, and 26 weeks of are, similar to human pancreatic intraepithelial neoplasias (PanINs)
(J:87196)
• PanINs increase in number and size with age, however no invasive tumors are seen up to 30 weeks of age
(J:87196)
• no evidence of neoplasia in the acinar cell compartment, however focal reactive metaplastic changes are seen
(J:87196)
• low-grade mPanIN lesions are seen in 3 month old mutants and by 6 months of age, most mice exhibit mPanIN lesions
(J:164210)
|
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• pancreatic islets are moderately enlarged but do not show evidence of neoplasia
|
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• average cancer free survival is greater than 52 weeks and 2 of 9 mice develop pancreatic ductal adenocarcinoma
(J:116130)
• 2 of 11 mutants show evidence of pancreatic ductal adenocarcinoma at 6 months of age, but not at earlier times
(J:164210)
|
|
• pancreatic ductal lesions are seen at 9, 12, 18, and 26 weeks of are, similar to human pancreatic intraepithelial neoplasias (PanINs)
(J:87196)
• PanINs increase in number and size with age, however no invasive tumors are seen up to 30 weeks of age
(J:87196)
• no evidence of neoplasia in the acinar cell compartment, however focal reactive metaplastic changes are seen
(J:87196)
• low-grade mPanIN lesions are seen in 3 month old mutants and by 6 months of age, most mice exhibit mPanIN lesions
(J:164210)
|
|
• acinar-to-ductal metaplasia is seen at 1 week of age
|
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• most mutants exhibit abdominal distention due to ascites fluid and pancreatic enlargement
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• average tumor-free survival is 38 weeks
|
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• 6 of 10 mice develop pancreatic ductal adenocarcinoma
|
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• 6 of 10 mice develop pancreatic ductal adenocarcinoma
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at about 2-3 months of age, mutants show signs of illness, with wasting, respiratory distress and frequently die before 6 months of age
|
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• mice exhibit ductal metaplasia that appears to result from expansion of centroacinar cells rather than transdifferentiation of acinar cells
|
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• mutants exhibit progressive replacement of the acinar pancreas with highly proliferative ductual structures that contain abundant mucins and markers of pancreatic progenitor cells
• preweaned mutants show a 4-fold increase in BrdU incorporation in the acinar pancreas, particularly in the centroacinar position and epithelial cells within large ducts, indicating increased proliferation
|
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• increase in centroacinar cells in the pancreas that are present in groups of 4-8 cells compared to single or doublet centroacinar cells in wild-type
|
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• increase in centroacinar cell proliferation and an increase in apoptosis of acinar cells in transitional areas
|
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• mice exhibit ductal metaplasia that appears to result from expansion of centroacinar cells rather than transdifferentiation of acinar cells
|
|
• mutants exhibit progressive replacement of the acinar pancreas with highly proliferative ductual structures that contain abundant mucins and markers of pancreatic progenitor cells
• preweaned mutants show a 4-fold increase in BrdU incorporation in the acinar pancreas, particularly in the centroacinar position and epithelial cells within large ducts, indicating increased proliferation
|
|
• increase in centroacinar cells in the pancreas that are present in groups of 4-8 cells compared to single or doublet centroacinar cells in wild-type
|
|
• increase in centroacinar cell proliferation and an increase in apoptosis of acinar cells in transitional areas
|
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• newborns exhibit enlarged and irregularly shaped islets
|
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• one 11-week old mutant developed papillary ductal adenocarcinoma while a 13-month old mutant developed a pancreatic ductal adenocarcinoma that invaded into the duodenum and exhibited a desmosplastic stroma
|
|
• mice exhibit widespread ductal metaplasia with increased mucin production and develop PanIN lesions and malignant transformation with low frequency
|
| N |
• fed and fasting blood glucose levels and glucose tolerance are normal
|
|
• mice exhibit widespread ductal metaplasia with increased mucin production and develop PanIN lesions and malignant transformation with low frequency
|
|
• 2 of 14 mice develop ductal malignancy in the pancreas
|
|
• one 11-week old mutant developed papillary ductal adenocarcinoma while a 13-month old mutant developed a pancreatic ductal adenocarcinoma that invaded into the duodenum and exhibited a desmosplastic stroma
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• invasive ductal adenocarcinomas with extensive regional and distant metastases
|
|
• invasive ductal adenocarcinomas with extensive regional and distant metastases
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| pancreatic carcinoma | DOID:4905 |
OMIM:260350 |
J:187012 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants develop pancreatic tumors with an average latency of 34.2 weeks
• 43% of tumors exhibit sarcomatoid differentiation
|
|
• 57% of tumors exhibit well differentiated ductal adenocarcinoma histology
|
|
• 69% of tumors exhibit metastasis
|
|
• mutants develop pancreatic tumors with an average latency of 34.2 weeks
• 43% of tumors exhibit sarcomatoid differentiation
|
|
• 57% of tumors exhibit well differentiated ductal adenocarcinoma histology
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• complete penetrance of death due to invasive and metastic cancer by 11 weeks of age
(J:87196)
• average tumor-free survival is 8.6 weeks
(J:116130)
|
|
• solid pancreatic tumors, frequently adhering to adjacent organs and the retroperitoneum
(J:87196)
• tumors are highly invasive, frequently involving the duodenum, stomach, liver and/or spleen and occasionally obstructing the common bile duct
(J:87196)
• 26% of tumors exhibit anaplastic carcinoma histology
(J:108298)
• 26% of tumors exhibit sarcomatoid differentiation
(J:108298)
|
|
• tumors exhibit pathologic features of human pancreatic ductal adenocarcinomas
(J:87196)
• 48% of tumors exhibit well differentiated ductal adenocarcinoma histology
(J:108298)
• 6 of 6 mice develop pancreatic ductal adenocarcinoma
(J:116130)
|
|
• earlier onset (3-4 weeks of age) of local premalignant ductal lesions (pancreatic intraepithelial neoplasia) than in mice just expressing the oncogenic form KRAS2 and not deficient for Cdkn2a expression
• pancreatic ductal lesions progress rapidly to invasive pancreatic adenocarcinoma
|
|
• neoplasms frequently invade the lymphatic and vascular system, indicating metastatic invasion
(J:87196)
• 11% of tumors exhibit metastasis
(J:108298)
|
|
• neoplasms rapidly progressed to become invasive and metastatic tumors
|
|
• solid pancreatic tumors, frequently adhering to adjacent organs and the retroperitoneum
(J:87196)
• tumors are highly invasive, frequently involving the duodenum, stomach, liver and/or spleen and occasionally obstructing the common bile duct
(J:87196)
• 26% of tumors exhibit anaplastic carcinoma histology
(J:108298)
• 26% of tumors exhibit sarcomatoid differentiation
(J:108298)
|
|
• tumors exhibit pathologic features of human pancreatic ductal adenocarcinomas
(J:87196)
• 48% of tumors exhibit well differentiated ductal adenocarcinoma histology
(J:108298)
• 6 of 6 mice develop pancreatic ductal adenocarcinoma
(J:116130)
|
|
• earlier onset (3-4 weeks of age) of local premalignant ductal lesions (pancreatic intraepithelial neoplasia) than in mice just expressing the oncogenic form KRAS2 and not deficient for Cdkn2a expression
• pancreatic ductal lesions progress rapidly to invasive pancreatic adenocarcinoma
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| pancreatic ductal adenocarcinoma | DOID:3498 | J:87196 , J:108298 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants develop pancreatic tumors with an average latency of 57 weeks
• 100% of tumors exhibit sarcomatoid carcinoma histology
|
|
• 67% of tumors exhibit metastasis
|
|
• mutants develop pancreatic tumors with an average latency of 57 weeks
• 100% of tumors exhibit sarcomatoid carcinoma histology
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Pancreatic tumors in Krastm4Tyj/Krastm4Tyj Trim33tm1Los/Trim33tm1Los Tg(Pdx1-cre)89.1Dam/0 and Krastm4Tyj/Krastm4Tyj Cdkn2atm4Rdp/Cdkn2atm4Rdp Tg(Pdx1-cre)89.1Dam/0 mice
|
• mice develop invasive pancreatic masses that are firm and homogeneous unlike in wild-type mice
|
|
• mice develop invasive pancreatic masses that are firm and homogeneous unlike in wild-type mice
|
|
• PET scans detected abnormal metabolic activity in the abdomen unlike in wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Accelerated pancreatic neoplasia in Krastm4Tyj/Krastm4Tyj Trim33tm1Los/Trim33tm1Los Tg(Pdx1-cre)89.1Dam/0 mice compared to Krastm4Tyj/Krastm4Tyj Tg(Pdx1-cre)89.1Dam/0 mice
|
• by 10 weeks
|
|
• at 6 weeks, cysts occupy 20% of the pancreatic space unlike in wild-type mice
|
|
• by 10 weeks
|
|
• at 6 weeks, cysts occupy 20% of the pancreatic space unlike in wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• differentiation of exocrine lineages is impaired; progenitors remain trapped in an undifferentiated state
|
|
• differentiation of exocrine lineages is impaired; progenitors remain trapped in an undifferentiated state
|
|
• differentiation of endocrine lineages is impaired; progenitors remain trapped in an undifferentiated state
|
|
• at E15.5, alpha cell numbers are reduced 8-fold
|
|
• at E15.5, beta cell numbers are reduced nearly 100-fold
|
|
• pancreatic epithelium at E17.5 is translucent, cystic and comprised of highly branched, tubular epithelium with few distinct acini
• newborn pancreas exhibits convoluted epithelium in a fibroblastic stroma instead of acinar and islet tissue
• differentiation of exocrine and endocrine progenitor cells is impaired
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• differentiation of pancreatic progenitor cells to endocrine (islet) or exocrine (acinar) lineage is blocked, and cyst-like structures form with Notch1 activation at E9.5
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• disrupted architecture of islets as evidenced by the migration of glucagon-expressing alpha-cells into the central region of the islets
|
|
• mild glucose intolerance in mice older than 6 months
• slightly more glucose intolerant during pregnancy than their control littermates
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• disrupted architecture of islets as evidenced by the migration of glucagon-expressing alpha-cells into the central region of the islets
|
|
• mild glucose intolerance in mice older than 6 months
• slightly more glucose intolerant during pregnancy than their control littermates
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 50% of mice are dead by 14 months of age unlike wild-type mice
|
|
• at 3 and 12 months, the vasculature of some islets is abnormal with dilation of blood vessels and intense tortuosity unlike in wild-type mice
• however, treatment with sunitinib decreases in islet vascularity
|
|
• as early as 5 to 6 months
|
|
• as early as 5 to 6 months
|
|
• by 10 to 12 months of age, mice develop insulinoma that are filled with blood islands or lacunae unlike wild-type mice
• however, mice do not develop gastrinoma unlike in other MEN1 models
|
|
• mice exhibit more proliferating cells within their islets compared with wild-type mice
• however, proliferation of exocrine cells is normal and treatment with sunitinib decreases islet cell proliferation
|
|
• at 10 months of age
|
|
• starting at 5 months of age
|
|
• by 10 to 12 months of age, mice develop insulinoma that are filled with blood islands or lacunae unlike wild-type mice
• however, mice do not develop gastrinoma unlike in other MEN1 models
|
|
• at 3 and 12 months, the vasculature of some islets is abnormal with dilation of blood vessels and intense tortuosity unlike in wild-type mice
• however, treatment with sunitinib decreases in islet vascularity
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| multiple endocrine neoplasia type 1 | DOID:10017 |
OMIM:131100 |
J:146440 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• metaplastic lesions are observed with contributions from acinar and ductal cells consistent with active acinar-ductal transdifferentiation
|
|
• at P1 acinar units are less compact with distended lumens; in some regions, acinar units are fragmented and intermixed with endocrine cells
|
|
• from P2 to P8, a rapid loss of acinar cells is observed, associated with appearance of abnormal ductal structures
|
|
• at P3, TUNEL assays reveal an 18-fold increase in acinar cell death in the pancreas relative to controls
|
|
• metaplastic lesions are observed with contributions from acinar and ductal cells consistent with active acinar-ductal transdifferentiation
|
|
• at P1 acinar units are less compact with distended lumens; in some regions, acinar units are fragmented and intermixed with endocrine cells
|
|
• from P2 to P8, a rapid loss of acinar cells is observed, associated with appearance of abnormal ductal structures
|
|
• islets are smaller and less well aggregated at P1 with a more diffuse distribution relative to wild-type; aggregation of islets is delayed with accumulation of smaller islets by P16
• at P1, there are decreased numbers of alpha, beta, and delta cells in the pancreas
|
|
• at P1
|
|
• at P1
|
|
• at P1
|
|
• islets are smaller and less well aggregated at P1 with a more diffuse distribution relative to wild-type; aggregation of islets is delayed with accumulation of smaller islets by P16
|
|
• at P1, pancreas is smaller than in littermate controls
|
|
• from P2 to P8, reactive fibrosis is observed in conjunction with acinar cell loss and abnormal ductal structures
|
|
• at P1, mice have elevated blood glucose levels but these return to normal by P8
|
|
• adult mutants show improved beta cell function relative to wild-type with faster clearance of blood glucose
|
|
• at P3, TUNEL assays reveal an 18-fold increase in acinar cell death in the pancreas relative to controls
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Peutz-Jeghers syndrome | DOID:3852 |
OMIM:175200 |
J:134078 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at E18.5, primary cilia are decreased in number and do not protrude into the duct lumen unlike in wild-type mice
|
|
• at E18.5, primary cilia are decreased in number and do not protrude into the duct lumen unlike in wild-type mice
• at E18.5 and 6 weeks of age, pancreatic ducts exhibit a dramatic decrease in cilia number compared with wild-type mice
|
|
• mice lacking cysts exhibit minimal branching in the dorsal pancreas and/or twisted irregular ducts and calcifications unlike in wild-type mice
|
|
• at E18.5, primary cilia are decreased in number and do not protrude into the duct lumen unlike in wild-type mice
|
|
• at E18.5, primary cilia are decreased in number and do not protrude into the duct lumen unlike in wild-type mice
• at E18.5 and 6 weeks of age, pancreatic ducts exhibit a dramatic decrease in cilia number compared with wild-type mice
|
|
• from 3 to 6 weeks of age, mice exhibit pancreatitis with atrophy, loss of acinar tissue, and acinar inflammation unlike in wild-type mice
|
|
• in mice with cysts
|
|
• at E18.5, primary cilia are decreased in number and do not protrude into the duct lumen unlike in wild-type mice
• at E18.5 and 6 weeks of age, mice exhibit a dramatic decrease in cilia number compared with wild-type mice
• pancreatic ducts become highly tortuous unlike in wild-type mice
• pancreatic ducts exhibit periductal inflammation, hemorrhage, and fibrosis
|
|
• by 6 weeks of age, the ductal epithelium is multilayered and dilated unlike in wild-type mice
|
|
• from 3 to 6 weeks of age
|
|
• at E18.5 but not E13.5 or E14.5
|
|
• at E18.5 but not E13.5 or E14.5
|
|
• mice lack definitive islets unlike wild-type mice
|
|
• at E14.5, pancreatic epithelium has less branching than in wild-type mice and fails to fully extend towards the distal surrounding mesenchyme
• postnatally, pancreatic epithelium never fills the mesenchyme unlike in wild-type mice
|
|
• mice exhibit dystrophic calcifications in adjacent fat unlike in wild-type mice
|
|
• at E18.5, mice develop a single, fluid-filled cyst lined with cuboidal epithelium in the dorsal pancreas unlike wild-type mice
• by 6 weeks of age, 63% of mice exhibit large pancreatic cysts mainly in the dorsal pancreas unlike wild-type mice
|
|
• in pancreatic ducts
|
|
• by P2, all mice exhibit acinar to ductal metaplasia unlike wild-type mice
|
|
• at E17.5 and 6 weeks of age, proliferation of ductal cells is increased compared to in wild-type mice
|
|
• from 3 to 6 weeks of age, mice exhibit pancreatitis with atrophy, loss of acinar tissue, and acinar inflammation unlike in wild-type mice
• mice exhibit neutrophils in peripancreatic fat; neutrophils in the lumen and ductal epithelium of smaller ducts; intraparenchymal mixed inflammatory infiltrate with neutrophils and lymphocytes, with areas of acinar injury; neutrophils scattered in periductal stroma; large ducts with erosion and acute inflammation unlike wild-type mice
|
|
• impaired glucose homeostasis worsens with age
|
|
• at P2 and 3.5 weeks of age, mice exhibit elevated random blood glucose levels compared with wild-type mice
• at 6 weeks of age, fasting blood glucose levels are higher than in wild-type mice
|
|
• in pancreatic ducts
|
|
• from 3 to 6 weeks of age, mice exhibit pancreatitis with atrophy, loss of acinar tissue, and acinar inflammation unlike in wild-type mice
• mice exhibit neutrophils in peripancreatic fat; neutrophils in the lumen and ductal epithelium of smaller ducts; intraparenchymal mixed inflammatory infiltrate with neutrophils and lymphocytes, with areas of acinar injury; neutrophils scattered in periductal stroma; large ducts with erosion and acute inflammation unlike wild-type mice
|
|
• from 3 to 6 weeks of age, mice exhibit pancreatitis with atrophy, loss of acinar tissue, and acinar inflammation unlike in wild-type mice
|
|
• in mice with cysts
|
|
• at E18.5, primary cilia are decreased in number and do not protrude into the duct lumen unlike in wild-type mice
• at E18.5 and 6 weeks of age, mice exhibit a dramatic decrease in cilia number compared with wild-type mice
• pancreatic ducts become highly tortuous unlike in wild-type mice
• pancreatic ducts exhibit periductal inflammation, hemorrhage, and fibrosis
|
|
• by 6 weeks of age, the ductal epithelium is multilayered and dilated unlike in wild-type mice
|
|
• from 3 to 6 weeks of age
|
|
• at E18.5, mice develop a single, fluid-filled cyst lined with cuboidal epithelium in the dorsal pancreas unlike wild-type mice
• by 6 weeks of age, 63% of mice exhibit large pancreatic cysts mainly in the dorsal pancreas unlike wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• average tumor-free survival is 12.6 weeks
|
|
• 4 of 12 mice develop intraductal papillary mucinous neoplasms
• tumor fibrosis is increased compared to mice wild-type for Smad4
|
|
• 8 of 12 mice develop gastric cancer
|
|
• 4 of 12 mice develop pancreatic ductal adenocarcinoma
• the proportion of undifferentiated carcinomas is decreased compared to mice wild-type for Smad4
|
|
• 8 of 12 mice develop gastric cancer
|
|
• 4 of 12 mice develop pancreatic ductal adenocarcinoma
• the proportion of undifferentiated carcinomas is decreased compared to mice wild-type for Smad4
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 5 of 8 mice develop gastric cancer with squamous or adenosquamous histology
|
|
• mice die between 8 and 24 weeks of age
• average tumor-free survival is 13.1 weeks
|
|
• seen in all mice
|
|
• seen in all mice
|
|
• 5 of 8 mice develop intraductal papillary mucinous neoplasms
|
|
• 5 of 8 mice develop gastric cancer with squamous or adenosquamous histology
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• average tumor-free survival is 7.4 weeks
|
|
• 3 of 10 mice develop intraductal papillary mucinous neoplasms
• tumor fibrosis is increased compared to mice wild-type for Smad4
|
|
• 5 of 10 mice develop gastric cancer
|
|
• 9 of 10 mice develop pancreatic ductal adenocarcinoma
• the proportion of undifferentiated carcinomas is decreased compared to mice wild-type for Smad4
|
|
• 5 of 10 mice develop gastric cancer
|
|
• 9 of 10 mice develop pancreatic ductal adenocarcinoma
• the proportion of undifferentiated carcinomas is decreased compared to mice wild-type for Smad4
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• reduced immunohistochemistry at E15.5 in the pancreas
|
|
• reduced immunohistochemistry at E15.5 in the pancreas
|
|
• reduced immunohistochemistry at E15.5 in the pancreas
|
|
• reduced immunohistochemistry at E15.5 in the pancreas
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• pancreatic development, morphology, and function are all similar to wild-type and no pancreatic neoplasms develop
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice are significantly leaner than control mice at 2, 4 and 8 months of age
• body weight is significantly lower than in control mice under high fat diet (HFD) conditions
|
| N |
• unexpectedly, fasted and randomly fed plasma glucagon and plasma insulin levels are similar to those in control mice at 4 months of age
• moreover, plasma glucagon levels remain unchanged even under severely hypoglycemic conditions
|
|
• mice show significantly lower blood glucose levels after both fasting and random feeding relative to controls at 4 months of age
• blood glucose levels are lower primarily during the later period of the insulin tolerance test; however, both c-fos activation in the hypothalamus and plasma catecholamine levels in response to hypoglycemia are normal
|
|
• during cold exposure mice maintain a higher body temperature than control mice
|
|
• energy expenditure is increased due to increased sympathetic tone and conversion from WAT to BAT relative to controls
• however, 24 h locomotor activity is normal with no changes during the light and dark phases at 8 months of age
|
|
• significantly higher carbon dioxide production than control mice at 8 months of age
|
|
• significantly higher oxygen consumption than control mice during both the light and dark phases at 8 months of age
• accumulated oxygen consumption during the light or dark phase and 24 h oxygen consumption are also increased relative to controls
|
|
• significantly higher average respiratory exchange rate than control mice at 8 months of age
|
|
• mice show significantly better glucose tolerance than control mice at 2, 4 and 8 months of age
• glucose tolerance and insulin tolerance tend to be better than in control mice under HFD conditions
|
|
• mice show significantly higher insulin sensitivity than control mice at 2, 4 and 8 months of age
• insulin-induced AKT phosphorylation in liver and skeletal muscle is increased relative to controls at 4 months of age
|
|
• significantly higher heat production during the dark phase and 24 h period than control mice at 8 months of age
|
|
• subcutaneous fat mass (adiposity %) is significantly reduced relative to controls
|
|
• significantly reduced inguinal and epididymal white adipose tissue weight at 8 months of age
• however, brown adipose tissue weight, lean body mass and body length are normal
|
|
• visceral fat mass (adiposity %) is significantly reduced relative to controls
|
|
• after cold exposure, mice show increased UCP1-expressing adipocytes in the inguinal WAT but not the epididymal WAT relative to controls
|
|
• epididymal white adipose tissue weight is significantly reduced at 8 months of age
|
|
• inguinal white adipose tissue weight is significantly reduced at 8 months of age
|
|
• increased sympathetic activity in adipose tissues causes browning of WAT i.e. conversion from WAT to BAT
|
|
• daily food intake is significantly reduced during both the dark and light phases at 7 months of age
|
|
• during cold exposure mice maintain a higher body temperature than control mice, indicating a higher sympathetic tone
• expression levels of adrenergic receptors are increased in brown adipose tissue, epididymal white adipose tissue, and skeletal muscle relative to controls
|
|
• mice show significantly lower Agrp mRNA levels than control mice in the hypothalamus after 24 h of fasting
|
|
• subcutaneous fat mass (adiposity %) is significantly reduced relative to controls
|
| N |
• mice show normal pancreatic glucagon and insulin secretion in response to changes in glucose concentration relative to controls
• no changes in beta and alpha cell mass, islet cell proliferation or apoptosis are observed
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Vhltm1Lss/Vhltm1Lss Tg(Pdx1-cre)89.1Dam/0 mice develop microcystic adenomas in the pancreas
|
• numbers of mutant offspring identified at weaning (3.7%) are significantly lower than expected Mendelian numbers (25%)
• expected numbers of double mutant offspring are present embryonically and at birth, but many die by P5
|
|
• at 6-7 months of age, pancreases are indistinguishable from controls; at 16-18 months of age, microcystic adenomas (MCA) are identified; extensive vasculature network is observed in MCA, similar to what is seen in human VHL patients
|
|
• at 16-18 months of age, significant loss of exocrine pancreas and replacement with fat deposition is observed
|
|
• at 16-18 months of age, some islets appear small and abnormally shaped without many exocrine acinar cells surrounding them
|
|
• at 6-7 months of age, pancreases are indistinguishable from controls; at 16-18 months of age, microcystic adenomas (MCA) are identified; extensive vasculature network is observed in MCA, similar to what is seen in human VHL patients
|
|
• at 6-7 months of age, pancreases are indistinguishable from controls; at 16-18 months of age, cysts are identified
|
|
• at 16-18 months of age, significant loss of exocrine pancreas and replacement with fat deposition is observed
|
|
• at 6-7 months of age, pancreases are indistinguishable from controls; at 16-18 months of age, cysts are identified
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| von Hippel-Lindau disease | DOID:14175 |
OMIM:193300 |
J:148174 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
 |
• 13% of males are diabetic at 9 weeks of age
|
|
|
• total pancreatic insulin content is decreased in males at 6 and 9 weeks of age, and is only 30% of control levels at 9 weeks
|
|
|
• 29% of males develop impaired glucose tolerance at 6 weeks of age, as indicated by elevated blood glucose levels at 30, 60, 90, and 120 minutes of an intraperitoneal glucose tolerance test
• 53% of males are glucose intolerant by 9 weeks of age
• females, however, exhibit normal intraperitoneal glucose tolerance test
|
|
|
• decrease in beta-cell proliferation at 4, 6, and 9 weeks of age
|
|
|
• in some glucose intolerant males at 6 weeks of age, the exocrine nuclei are enlarged and the islets look smaller
• in 9 week old diabetic males, cysts are present in the exocrine pancreas
• orientation of exocrine cells is irregular and nuclei of disorganized exocrine cells are enlarged in 9 week old diabetic males
|
|
|
• at 9 weeks of age, pancreas from diabetic males shows alteration in islet architecture, with a decrease in insulin-producing cells, an increase in alpha-cells and scattering of alpha-cells throughout the islets rather than at the periphery
• pancreas from males with impaired glucose tolerance or diabetes shows an increase in intra-islet keratin-positive cells, suggesting that islets contain cells with a ductal phenotype
|
|
|
• at 9 weeks of age, pancreas from diabetic males shows an increase in alpha-cells
|
|
|
• although the average beta-cell size per pancreas is the same as in controls at 9 weeks, the average beta-cell size per islet is variable, with some islets composed mainly of beta-cells that are much larger than the average and others composed of beta-cells less than 60 um2, indicating that some beta-cells are undergoing hypertrophy and others are dying
|
|
• decrease in beta-cell mass is seen at 4, 6, and 9 weeks of age compared to controls: mice show an initial increase in beta-cell mass from P1 to 4 weeks of age and thereafter remain the same or slightly decreased compared to controls which show continued beta cell mass increase from P1 to 9 weeks
• beta-cell mass of males is only about 30% of controls at 9 weeks of age
• females show an approximate 20% decrease in beta-cell mass at 9 weeks of age
|
|
|
• pancreas from males show a gradual loss of insulin-producing cells
|
|
• islet size in both males and females is smaller than controls at 9 weeks of age
|
|
|
• whole pancreatic wet weights are slightly but significantly lower in males at 9 weeks of age
|
|
|
• in 9 week old diabetic males, cysts are present in the exocrine pancreas; cysts are negative for oil red O staining indicating that they are not adipose accumulations and are most likely due to necrotic cell death
|
|
|
• exocrine tissue from diabetic males shows many enlarged cells undergoing lysis and losing membrane integrity, signs of cellular necrosis
|
|
|
• total pancreatic insulin content is decreased in males at 6 and 9 weeks of age, and is only 30% of control levels at 9 weeks
|
|
|
• decrease in beta-cell proliferation at 4, 6, and 9 weeks of age
|
|
|
• in some glucose intolerant males at 6 weeks of age, the exocrine nuclei are enlarged and the islets look smaller
• in 9 week old diabetic males, cysts are present in the exocrine pancreas
• orientation of exocrine cells is irregular and nuclei of disorganized exocrine cells are enlarged in 9 week old diabetic males
|
|
|
• in 9 week old diabetic males, cysts are present in the exocrine pancreas; cysts are negative for oil red O staining indicating that they are not adipose accumulations and are most likely due to necrotic cell death
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| type 2 diabetes mellitus | DOID:9352 |
OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036 |
J:111026 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice fed a high-fat diet for 20 weeks exhibit enhanced beta-cell mass
|
|
• in mice fed a high-fat diet for 20 weeks
|
|
• islets in vitro show lower insulin secretion at low glucose and greater insulin secretion at high glucose after 24 hours of cytokine treatment compared to wild-type islets, indicating that islets exhibit resistance to cytokine toxicity in vitro
|
|
• mice fed a high-fat diet for 20 weeks exhibit reduced beta cell death compared to controls
|
|
• mice fed a high-fat diet for 20 weeks exhibit improved insulin secretion after glucose injections
|
|
• mice fed a high-fat diet for 20 weeks exhibit improved insulin secretion after glucose injections
|
|
• mice fed a high-fat diet for 20 weeks show increased islet antioxidant enzyme levels
|
|
• STZ-treated mice show improved glucose tolerance
• mice fed a high-fat diet for 20 weeks are protected from glycemic deterioration, showing glucose tolerance similar to mice fed a normal chow diet and higher insulin levels after glucose injections
|
|
|
• males injected with low-dose streptozotocin (STZ) show an initial hyperglycemia by day 10 of STZ treatment as seen in controls but thereafter blood glucose remain stable and do not worsen as in controls, indicating protection from STZ-induced glycemic deterioration
|
|
• islets in vitro show almost completely blocked ROS production after 24 hours of cytokine treatment and marker analysis of islets shows that they are protected from chronic cytokine-induced oxidative and ER stress
• mice fed a high-fat diet for 20 weeks show decreased islet oxidative stress and increased antioxidant enzyme levels
|
| N |
• mice fed a high-fat diet for 20 weeks exhibit similar weight and percent fat mass as controls and show no differences in adipocyte size or macrophage infiltration into adipocytes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 20 weeks in glucose and GLP-1-stimulated islets
|
|
• at 20 weeks after intraperitoneal injection of glucose
|
|
• at 12 weeks upon oral glucose challenge
• at 20 weeks upon intraperitoneal injection of glucose
• in mice fed a high fat diet upon intraperitoneal injection of glucose
|
|
• in mice fed a high fat diet
|
|
• at 20 weeks in glucose and GLP-1-stimulated islets
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at P28 and P56, pancreatic insulin content is reduced compared to in wild-type mice
• however, insulin content at P1 is normal
|
|
• at P56
|
|
• unstimulated and glucose-stimulated beta cells increased docking and release of secretory vesicles compared with wild-type cells
• however, the total number of vesicles is normal
|
|
• in stimulated pancreatic islet cells
|
|
• in stimulated pancreatic islet cells
|
|
• after glucose challenge
|
|
• in an intraperitoneal glucose tolerance test, mice exhibit improved glucose clearance compared with wild-type mice
• pertussis toxin-treated mice fail to exhibit an increase in glucose tolerance unlike similarly treated wild-type mice
• however, insulin sensitivity is normal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• islet cell exhibit normal architecture and beta cell proliferation is normal
|
| N |
• mice exhibit normal glucose homeostasis
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at E12.5 branching structures fail to form, although pancreatic fate is normally specified
• at E12.5 but not at E11.5 proliferation is decreased mainly due to a decrease in proliferation of pancreatic progenitor cells
• epithelial cells fail to remodel and instead remain stratified with cuboidal shape and disorderly arrangement possibly due to a defect in actomyosin cytoskeletal organization
• both endocrine and exocrine cells similarly affected
• at E16.5 ducts and acini appear as malformed large cellular aggregates
• cultured explants fail to form tubular aggregates under conditions where wild-type explants form aggregates; however, in the presence of C3 ribosyltransferase mutant explants will form tubular aggregates
|
|
• show a slower and delayed return to basal levels after glucose challenge
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• reduced pancreatic intraepithelial neoplasia incidence and tumor size compared with Krasem1Gpt/ Kras+ Tg(Pdx1-cre)89.1Dam mice
|
|
• reduced pancreatic intraepithelial neoplasia incidence and tumor size compared with Krasem1Gpt/ Kras+ Tg(Pdx1-cre)89.1Dam mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• reduced pancreatic intraepithelial neoplasia incidence at both 6 and 9 months of age compared with Krasem1Gpt/ Kras+ Tg(Pdx1-cre)89.1Dam mice
|
|
• reduced pancreatic intraepithelial neoplasia incidence at both 6 and 9 months of age compared with Krasem1Gpt/ Kras+ Tg(Pdx1-cre)89.1Dam mice
|
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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