Mouse Genome Informatics
cn1
    Rb1tm3Tyj/Rb1tm3Tyj
Tg(tetO-MYC)36aBop/0
Tg(Cebpb-tTA)5Bjd/0

involves: FVB/N * NMRI
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
• following withdrawal of doxycycline and intrasplenic injection of adenovirus expressing Cre recombinase, adult liver cells exhibit an increase in polyploidy

mortality/aging
• median survival of mutants is 27 weeks following withdrawal of doxycycline and intrasplenic injection of adenovirus expressing Cre recombinase
• median survival of mutants with tumors is 16.5 weeks following withdrawal of doxycycline and intrasplenic injection of adenovirus expressing Cre recombinase

tumorigenesis
• following withdrawal of doxycycline and intrasplenic injection of adenovirus expressing Cre recombinase, some mice develop liver tumors composed of multiple fleshy vascular nodules
• tumors of mice injected with adenovirus expressing Cre recombinase and without doxycycline to induce MYC expression are composed of hepatocellular neoplasms characterized by sheets of cells with occasional mitotic figure, slightly pleomorphic nuclei, and prominent nucleoli
• tumors show a range of differentiation between well- and moderately-differentiated hepatocellular carcinoma

Mouse Models of Human Disease
OMIM IDRef(s)
Hepatocellular Carcinoma 114550 J:172430


Mouse Genome Informatics
cx2
    Dbttm1Geh/Dbttm1Geh
Tg(tetO-DBT)A1Geh/0
Tg(Cebpb-tTA)5Bjd/0

involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB * NMRI
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• approximately 4% of pups surviving to weaning have this genotype, compared to a theoretical survival rate or 14%, indicating partial rescue of the Dbttm1Geh phenotype
• transgenic mice survival is only ~16 weeks, when mice become moribund and are sacrificed

homeostasis/metabolism
• blood levels of alanine, glutamate, and glutamine are reduced compared to controls, but greater than in Dbttm1Geh homozygous mice
• BCAA/alanine (BCAA -branched-chain amino acids - leucine + isoleucine + valine) values are intermediate between controls and Dbt-null mice between 4-7 weeks of age
• levels of branched-chain keto acid dehydrogenase (BCKDH) activity are only 5-6% of controls levels, despite nearly equal protein levels, indicating suboptimal BCKDH activity of protein assembled with human E2

Mouse Models of Human Disease
OMIM IDRef(s)
Maple Syrup Urine Disease; MSUD 248600 J:119973


Mouse Genome Informatics
cx3
    Dbttm1Geh/Dbttm1Geh
Tg(tetO-DBT)525AGeh/0
Tg(Cebpb-tTA)5Bjd/0

involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB * NMRI
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• approximately 11% of pups surviving to weaning have this genotype, compared to a theoretical survival rate or 14%, indicating high degree of rescue of the Dbt-deficient phenotype
• only 12% (2/16) transgenic mice survive to 20 weeks; two surviving mice live to 40 and 60 weeks, respectively

homeostasis/metabolism
• blood levels of glutamate are reduced compared to controls, but greater than in Dbttm1Geh homozygotes
• BCAA/alanine (BCAA -branched-chain amino acids - leucine + isoleucine + valine) values are intermediate between controls and Dbttm1Geh homozygotes between 4-10 weeks of age

Mouse Models of Human Disease
OMIM IDRef(s)
Maple Syrup Urine Disease; MSUD 248600 J:119973


Mouse Genome Informatics
cx4
    Kdrtm1Jrt/Kdr+
Tg(tetO-Kdr*)4377.5Rwng/0
Tg(Cebpb-tTA)5Bjd/0

involves: 129S1/Sv * 129X1/SvJ * FVB/N * NMRI
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
liver/biliary system
• at E12.5, liver vasculature is less organized and vessels are dilated
• at E13.5, microvascular network is more disorganized with fewer branches than in control livers; newborns have very little microvascular network is observed


Mouse Genome Informatics
cx5
    Tg(tetO-Kdr*)4377.5Rwng/0
Tg(Cebpb-tTA)5Bjd/0

involves: FVB/N * NMRI
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• between 25% and 38% of pups are stillborn

liver/biliary system
N
• liver glycogen and albumin levels are comparable to control animals (J:100427)
• livers from neonates display a decrease in blood vessels
• livers of all newborn animals are dark red in appearance in contrast to pink color of control livers
• fewer endothelial cells (ECs) are present in mutant liver vasculature; ECs are present but are less organized and more discontinuous than in controls
• fewer or collapsed-appearing sinusoidal channels are observed
• livers have a sparse and poorly developed sinusoidal network with numerous blood cells in the disrupted sinusoidal spaces
• parenchymal cells contain very few or no lipid droplets
• morphology of space of Disse is abnormal, showing large gaps between sinusoidal epithelial cells (SECs) and hepatocytes
• sinusoidal epithelium lacks fenestrations seen in normal livers
• hepatocytes are more scattered than in control livers and many are oddly shaped with fewer microvilli projections into the space of Disse
• there is increase in red blood cells in liver due to defective circulation
• livers show a significant defect in lipoprotein uptake compared to controls
• 30 to 63% of newborns are jaundiced; suppression of transgenic Kdr by doxycycline treatement of dams during embryogenesis eliminates jaundice that is observed in untreated animals

cardiovascular system
• decreased number of blood vessels in liver

homeostasis/metabolism
N
• serum bilirubin levels are normal (J:100427)


Mouse Genome Informatics
cx6
    Tg(tetO-MET)23Rwng/0
Tg(Cebpb-tTA)5Bjd/0

involves: FVB/N * NMRI
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice from 2 lines (1 and 2) of double transgenic founders die within 2 months postpartum; early mortality can be prevented by repression of MET expression with doxycycline administration to mating parents, and then to pups until 4 weeks of age
• with this doxycycline treatment, animals appear normal until 10 months of age, then mice start dying
• mice from 2 other lines (3 and 4) of double transgenic parents are healthy at birth, then begin to die at 4 months of age

growth/size
• animals dying without evidence of tumors are usually cachexic

liver/biliary system
• hepatocytes in foci of hyperplasia develop foamy cytoplasm containing fat deposits
• with progression of hyperplastic foci toward malignancy, cytologic changes are observed such as cellular and nuclear enlargement with disorganization of cell plate and lobular structures; malignant foci enlarge and develop trabeculae lined with endothelial cells, often separated from each other by blood-filled spaces
• pups are born with enlarged and fatty livers
• fully developed tumors often display areas of necrosis
• pups are born with enlarged and fatty livers
• animals dying without evidence of tumors display jaundice

tumorigenesis
• 85% of animals dying after 10 months after receiving DOX till 4 weeks of age show hepatocellular carcinoma (HCC); incidence by 1 year is >60% in lines 1 and 2
• for lines 3 and 4, 85% of deaths are accompanied by HCC, which appears as an abdominal mass at 6 months of age or later; incidence by 1 year is 60%
• by 60 weeks of age, many small foci of hyperplasia are detected, often around central hepatic lobule and become more numerous, larger, and uniformly distributed by 4 months of age
• zones of progression to malignancy are observed within hyperplasias by 6 months, with cells in the zones showing poor organization and less differentiation than normal livers
• majority of moribund mice treated with doxycycline regain health tumors nearly regress completely, with liver morphology becoming almost normal by 4 months of treatment
• fully developed tumors often display areas of necrosis

Mouse Models of Human Disease
OMIM IDRef(s)
Hepatocellular Carcinoma 114550 J:69731


Mouse Genome Informatics
cx7
    Tg(tetO-MYC)36aBop/0
Tg(Cebpb-tTA)5Bjd/0

involves: FVB/N * NMRI
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• following withdrawal of doxycycline, all mice succumb to liver tumors within 2 weeks (J:93899)
• median survival of mutants is 31 weeks following doxycycline withdrawal to induce MYC expression (J:172430)
• median survival of mutants with tumors is 27 weeks following doxycycline withdrawal to induce MYC expression (J:172430)

tumorigenesis
• doxycycline-treated mice infected with an adeno-associated virus-expressing Mir122 exhibit suppression of tumorigenesis tumor cell proliferation compared with control mice
• following withdrawal of doxycycline, mice develop tumors with a latency of 12 weeks and all mice succumb to liver tumors within 2 weeks (J:93899)
• liver tumors that develop in mice after doxycycline withdrawal are invasive and metastasis into the thoracic cavity and lung parenchyma (J:93899)
• however, re-establishment of doxycycline-treatment produces rapid and sustained tumor regression (J:93899)
• repeated withdrawal and treatment with doxycyclineinduces and represses, respectively, tumor formation (J:93899)
• liver tumors that develop in mice after doxycycline withdrawal resemble hepatocellular carcinomas and/or hepatoblastomas
• liver tumors that develop in mice after doxycycline withdrawal resemble hepatocellular carcinomas and/or hepatoblastomas (J:93899)
• tumors that form in mice after doxycycline withdrawal are composed of hepatocellular neoplasms characterized by sheets of cells with occasional mitotic figure, slightly pleomorphic nuclei, and prominent nucleoli (J:172430)
• tumors show a range of differentiation between well- and moderately-differentiated hepatocellular carcinoma (J:172430)
• in doxycycline-treated mice (J:190067)
• however, treatment with adeno-associated virus-expressing Mir122 suppresses tumorigenesis (J:190067)

Mouse Models of Human Disease
OMIM IDRef(s)
Colorectal Cancer; CRC 114500 J:190067
Hepatocellular Carcinoma 114550 J:93899 , J:172430