Analysis Tools|
Allele Symbol Allele Name Allele ID |
Gt(ROSA)26Sortm1(Notch1)Dam targeted mutation 1, Douglas A Melton MGI:2684314 |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Summary |
22 genotypes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit rescue of growth retardation and osteosclerotic phenotypes seen in single Gt(ROSA)26Sortm1(Notch1)Dam conditional mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pancreatic progenitor cells (GFP +ve) form cystic structures, not narrow, branched structures, that lack endocrine or acinar marker expression with tamoxifen treatment (2 mg) at E9.5 or 11.5
• treatment at E13.5 or 15.5 blocks islet differentiation, but some exocrine differentiation occurs, with labeled cells integrating into normal acini and ducts
• treatment with 0.5 mg tamoxifen at E9.5 still results in formation of abnormal cystic tubules as seen with the higher dose
• Notch 1 activation at E13.5 results in most GFP +ve cells adopting a ductal, rather than acinar, fate; activation at E15.5 reverses the proportions with most cells taking an acinar fate
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• after 14 weeks of tamoxifen administration, neoplastic nodules form rapidly in the liver, presumably due to increased Notch1 signaling
|
|
• after 14 weeks of tamoxifen administration, neoplastic nodules form rapidly in the liver, presumably due to increased Notch1 signaling
|
|
• after 14 weeks of tamoxifen administration, neoplastic nodules form rapidly in the liver, presumably due to increased Notch1 signaling
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• tamoxifen treated and untreated mice develop widespread pancreatic intraepithelial neoplasia (PanIN) that develops from acinar cells
• PanINs proceed to more severe stages than in Krastm4Tyj/Krastm4Tyj Tg(Ela1-cre/ESR1)1Dam mice
• acinar-ductal metaplasia precedes PanIN
|
|
• tamoxifen treated and untreated mice develop widespread pancreatic intraepithelial neoplasia (PanIN) that develops from acinar cells
• PanINs proceed to more severe stages than in Krastm4Tyj/Krastm4Tyj Tg(Ela1-cre/ESR1)1Dam mice
• acinar-ductal metaplasia precedes PanIN
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice treated with tamoxifen staring at E10.5 exhibit pancreatic intraepithelial neoplasia (PanIN) that overtakes nearly all of the organ
• mice not treated with tamoxifen develop focal PanIN that are more numerous than in Krastm4Tyj/Krastm4Tyj Tg(Ipf1-cre/Esr1)35.10Dam mice
• acinar-ductal metaplasia precedes PanIN
|
|
• mice treated with tamoxifen staring at E10.5 exhibit pancreatic intraepithelial neoplasia (PanIN) that overtakes nearly all of the organ
• mice not treated with tamoxifen develop focal PanIN that are more numerous than in Krastm4Tyj/Krastm4Tyj Tg(Ipf1-cre/Esr1)35.10Dam mice
• acinar-ductal metaplasia precedes PanIN
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• brown adipose tissue shows hypertrophy, accompanied by presence of large unilocular adipocytes
|
| N |
• mice shown normal glucose metabolism, with reversal of hyperglycemia to a level that is lower than in wild-type mice and normalized response to glucose challenge
|
|
• mice develop malignant sarcomas by 3 months of age at various locations of the body, including diaphragm, limb, spine, retroperitoneum, subcutaneous regions, and in the thoracic cavity
• multiple tumors of various sizes are seen in all mice
• tumors show classical biphasic neoplasm with one component of atypical lipomatous tumors and a second component of high-grade sarcoma indicating dedifferentiated liposarcoma
• tumors show heavy infiltration of inflammatory cells which are Cd45+/Ki67-
• treatment with rosigliatazone starting from 3 weeks of age prevents liposarcoma formation at 5 months of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• unable to recover any viable embryos after E13.5
|
|
• pancreas shows absence of glucagon+ alpha cells at E13.5
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• sequential injection of tamoxifen to pregnant females at E13.5 and E14.5 to activate cre recombinase results in a pancreatic tubular epithelium devoid of endocrine and exocrine markers, indicating impaired differentiation of progenitor cells
• however, when tamoxifen is injected into adults, mature endocrine are not perturbed
|
|
|
| ♀ | 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 |
|
• pups lose weight, become hyperglycemic, and die by postnatal day 3 (P3)
|
| N |
• endocrine differentiation is not completely abrogated, as some chromogranin A stained cells expressing EGFP are detected; some endocrine cells express PPY, with a few expressing glucagon or coexpressing PYY, but no insulin-, somatostatin-, or PP-expressing cells are observed
|
|
• in contrast to normal pancreata where Neurog3-positive cells generate individual or pairs of duct cells, most EGFP-labeled cells are duct cells with Notch activation in 2-day old mice; no cells expressing both duct and endocrine markers are detected
• total numbers of duct cells are comparable to controls, but with Notch-activation, the fraction fated to duct lineage is substantially increased relative to cells fated to endocrine lineage
|
|
• islets fail to develop
|
|
• in contrast to normal pancreata where Neurog3-positive cells generate individual or pairs of duct cells, most EGFP-labeled cells are duct cells with Notch activation in 2-day old mice; no cells expressing both duct and endocrine markers are detected
• total numbers of duct cells are comparable to controls, but with Notch-activation, the fraction fated to duct lineage is substantially increased relative to cells fated to endocrine lineage
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die at E15.5
|
|
• reduced subepicardium thickness is detected at E14.5
|
|
• death is associated with pericardial bleeding (suggesting cardiac failure as cause of death)
|
|
• gaps in epicardium are usually associated with cysts and epicardial blistering
|
|
• death is associated with pericardial bleeding (suggesting cardiac failure as cause of death)
|
|
• reduced subepicardium thickness is detected at E14.5
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutant bone marrow transplanted chimeras survive to 250 days after pI-pC treatment
• decreased numbers of CD45.2+eGFP+ DP leukemic cells in the mutant bone marrow transplanted chimeras at 3 and 12 weeks
• CD45.2+eGFP+ DP leukemic cells disappear by 24 weeks
|
|
• decreased B220+ B cell numbers
|
|
• decreased B220+ B cell numbers
|
|
|
| ♀ | 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 |
|
• mutant bone marrow transplanted chimeras survive to 26 days after pI-pC treatment
|
|
• three weeks after pI-pC injection, the bone marrow is almost exclusively composed of CD45.2+eGFP+ DP leukemic cells in the mutant bone marrow transplanted chimeras
• infiltration of the spleens by leukemic DP cells
|
|
• severe splenomegaly in mutant bone marrow transplanted chimeras
|
|
• decreased B220+ B cell numbers in mutant bone marrow transplanted chimeras
|
|
• increased WBC counts in mutant bone marrow transplanted chimeras
|
|
• severe splenomegaly in mutant bone marrow transplanted chimeras
|
|
• decreased B220+ B cell numbers in mutant bone marrow transplanted chimeras
|
|
• increased WBC counts in mutant bone marrow transplanted chimeras
|
|
• severe splenomegaly in mutant bone marrow transplanted chimeras
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• with Notch activation, about 10% of islets have EGFP-positive cells not expressing chromogranin A (ie. non-endocrine cells); most of these cells are duct cells or in small intraislet ductules at ages P2 to 1 year
• no EGFP-labeled cells express amylase, indicating they are not of acinar lineage
|
|
• most islets are histologically indistinguishable from normal littermates, but some cells in the center of islets stain for hormones normally restricted to the islet periphery but not found in the core (glucagon, somatostatin, PP) whereas in normal islets, insulin staining is uniform in the core; this change in distribution is seen in most islets in 2-day old to 1yr old animals but total numbers of non-insulin expressing cells are not significantly changed
• non-insulin expressing endocrine cells in the islet cores do not coexpress insulin or MafA, suggesting they do not have properties of mature beta cells
• about 1-2% of EGFP-labeled cells are associated with large dilated cystic structures lined with cuboidal cell; large EGFP-expressing ducts are sometimes associated with islets and small intraislet ductiles within an adjacent islet
|
| N |
• mice are normoglycemic with normal glucose tolerance
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• tamoxifen induction in 8-week old mice did not result in observable differences in pancreatic cell types compared to controls; about 90% of EGFP-labeled (or EYFP-labeled (in Tg(Neurog3-cre/ERT2)1Able/ Gt(ROSA)26Sortm1(EYFP)Cos/+ mice) cells differentiate into insulin-expressing (chromogranin A stained) cells; differentiation is not affected in adult Neurog3-positive cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• smaller body weight at P24
|
|
• from 2 weeks of age, mice show progressive growth retardation
|
|
• thickened bones at 4 weeks of age
• cortices of bones are composed on woven bone in 2 month old mice
|
|
• increase in thickness of calvarial bone
|
|
• marrow space is enclosed by fibrotic cells with features of early osteoblastic precursors
|
|
• trabecular bone is composed predominately of immature woven rather than lamellar bone
• trabecular bone architecture is altered in 2 month old mice
|
|
• trabecular bone volume/tissue volume is increased by more than 6-fold in 2 month old mice
|
|
• increase in trabecular number in 2 month old mice
|
|
• decrease in trabecular spaces in 2 month old mice
|
|
• increase in trabecular bone thickness in 2 month old mice
|
|
• increase in bone mass due to increased bone formation
|
|
• generalized osteosclerotic phenotype in skulls, rib cages, tail vertebrae, and limb long bones
|
|
• from 2 weeks of age, mice show a kinky tail
|
|
• increase in thickness of calvarial bone
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice exhibit overproduction of a proximal tubule marker
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice develop solid tumors starting at 8 months of age at various locations of the body, including diaphragm, limb, spine, retroperitoneum, and subcutaneous regions
• by 13 months of age, all mice develop tumors
• tumors are identified as dedifferentiated liposarcomas
• treatment with rosigliatazone starting at 7 months of age prevents liposarcoma formation at 15 months of age
|
|
• epididymal white adipose tissue is not visible in mice older than 5 months of age
|
|
• adipose tissues of adults, but not 3 week old mice, express lower levels of mature adipocyte markers, indicating dedifferentiation of white adipocytes
• mice treated with rosiglitazone, show reactivation of mature adipocyte marker expression
|
|
• adults gradually develop lipodystrophy, resulting in an approximate 90% reduction of adipose tissue weights
• mice treated with rosiglitazone, a synthetic Ppar-gamma ligand and antidiabetic drug, show increased size and weight of adipose tissues
|
|
• adipose tissues of adults, but not 3 week old mice, express lower levels of mature adipocyte markers, indicating dedifferentiation of white adipocytes
• mice treated with rosiglitazone, show reactivation of mature adipocyte marker expression
|
|
• mice are resistant to high-fat diet-induced body weight gain
|
|
• mice are resistant to high-fat diet-induced body weight gain
|
|
• 15-fold and 40-fold increase in circulating insulin levels under fasted and re-fed conditions, respectively
• treatment with rosigliatazone rescues the diabetes
|
|
• 15-fold and 40-fold increase in circulating insulin levels under fasted and re-fed conditions, respectively, indicating severe insulin resistance
• mice fail to respond to insulin in all time points during the 2-hour insulin tolerance tests on both a chow diet and high-fat diet
|
|
• livers show very high fat content accompanied by elevated expression levels of genes involved in lipid metabolism
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice show normalization of obesity phenotype seen in single Lepob homozygotes
|
|
• mice exhibit very high blood glucose levels
|
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
||
|
Citing These Resources Funding Information Warranty Disclaimer, Privacy Notice, Licensing, & Copyright Send questions and comments to User Support. |
last database update 12/17/2024 MGI 6.24 |
|
|
|
||
