Mouse Genome Informatics
hm1
    Cav1tm1Mls/Cav1tm1Mls
B6.Cg-Cav1tm1Mls
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
endocrine/exocrine glands
• premature development of the lobuloalveolar compartment of the mammary gland during pregnancy (J:120010)
• however, serum prolactin levels are normal (J:120010)
• premature lactation; at day 18 of pregnancy, mammary glands of mutants are engorged with milk whereas wild-type glands are just beginning milk production and exhibit accelerated milk protein production (J:120010)

reproductive system
• premature development of the lobuloalveolar compartment of the mammary gland during pregnancy (J:120010)
• however, serum prolactin levels are normal (J:120010)

adipose tissue
• adipocytes lack caveolae
• mitochodria of brown adipocytes are larger and dilated and much less electron dense than mitochondria of wild-type mice
• adipocytes of brown adipose tissue contain larger lipid droplets than in wild-type mice

homeostasis/metabolism
• mutants show a decrease in body temperature in response to fasting or fasting/cold treatment, however cold treatment alone has no further effect on temperature
• mild, but significant, decrease in resting core body temperature
• mutants fail to exhibit the normal increase in serum nonesterifited fatty acids induced by fasting or fasting/cold treatment
• the reduction of triglyceride content of brown adipose tissue (BAT) induced after fasting/cold treatment is much lower than in controls (3-fold reduction in mutants vs. 10-fold reduction in controls), indicating defective release of stored triglycerides in BAT
• lipolysis fails to occur when mice are fasted or fasted/cold treated
• after fasting/cold treatments, BAT adipocytes of wild-type mice are devoid of lipid droplets while those of mutants still contain lipid droplets, indicating decreased lipid utilization after fasting/cold treatment

integument
• premature development of the lobuloalveolar compartment of the mammary gland during pregnancy (J:120010)
• however, serum prolactin levels are normal (J:120010)
• premature lactation; at day 18 of pregnancy, mammary glands of mutants are engorged with milk whereas wild-type glands are just beginning milk production and exhibit accelerated milk protein production (J:120010)

cardiovascular system
• absence of caveolae in microvascular endothelia (lung, heart and fat)
• gaps in the lung capillary

cellular
• absence of caveolae in microvascular endothelia (lung, heart and fat) and fat adipocyte

respiratory system
• gaps in the lung capillary


Mouse Genome Informatics
hm2
    Cav1tm1Mls/Cav1tm1Mls
B6.Cg-Cav1tm1Mls/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular

reproductive system
• Background Sensitivity: decrease in fertility on a C57BL/6J background

respiratory system
• presence of vascular-derived fluid in pulmonary tissues
• increase in collagen deposition in the lung parenchyma and the periphery of airways
• 60% increase in elastic fiber deposits in the lungs, with thicker layers of elastic fibers primarily around airways and arteries
• however, mutants do not exhibit emphysema
• 60% increase in elastic fiber deposits in the lungs, with thicker layers of elastic fibers primarily around airways and arteries
• from 3 months on, mutants exhibit a a sustained increase in lung elastance
• from 3 months on, mutants exhibit altered respiratory mechanics, suggesting stiffening of the lung tissue
• from 3 months on, mutants exhibit an increase in airway resistance
• from 3 months on, mutants exhibit a decrease in lung compliance

homeostasis/metabolism
• presence of vascular-derived fluid in pulmonary tissues

cardiovascular system
• increase in permeability of the pulmonary endothelial barrier to plasma proteins as indicated by an accumulation of proteins, especially albumin, in bronchoalveolar lavage from 1-9 months of age and leakage of Evans blue in pulmonary tissues


Mouse Genome Informatics
hm3
    Cav1tm1Mls/Cav1tm1Mls
FVB.Cg-Cav1tm1Mls
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• increase in lactate levels following 3-mercaptopicolinic acid treatment
• elevated circulating peroxide levels and a small decrease in circulating pyruvate levels
• when placed on a high fat diet
• elevated circulating branched-chain amino acid levels
• following 3-mercaptopicolinic acid treatment
• variability in the respiratory exchange ratio over a 24 hour period is reduced
• maintain glucose levels better in the fasted state better than wild-type controls
• exposure to 3-mercaptopicolinic acid causes a larger drop in glucose levels compared to wild-type mice
• upon refeeding display fairly severe hyperglycemia
• enhanced hepatic gluconeogenesis
• treatment with enoximone, a phospodiesterase inhibitor, potently increases glucose levels
• following a glycerol bolus, glycerol induced glucose production is enhanced but glycerol clearance is delayed
• in the fed state
• in moderately fasted mice
• reduced total circulating levels and a decrease in the proportion of the HMW form
• delay in suppression of free fatty acid levels following refeeding
• impaired beta3-AR agonist induced release of free fatty acids
• in fed and fasted mice

cellular
• MEFs display a preference for glycolysis in glucose-deprived media
• expression analysis indicates altered mitochondrial function
• mitochondria in MEFs display dramatically increased membrane potential
• however, mitochondria isolated from liver and lung tissue display similar function compared to wild-type controls

adipose tissue
• reduced fat mass
• enhanced uptake of leucine in mildly fasted mice

growth/size
• reduced fat mass
• lose more weight when fasted
• when placed on a high fat diet

behavior/neurological

muscle
• skeletal muscle tissue has a darker appearance indicating an increased mitochondrial content

liver/biliary system
• in the fed state
• in moderately fasted mice
• under all conditions tested
• fasting induced and high fat diet induced hepatic steatosis are reduced
• alternate day fasting has no effect of hepatic lipid content unlike in wild-type mice
• hepatic triglyceride synthesis appears to be reduced


Mouse Genome Informatics
hm4
    Cav1tm1Mls/Cav1tm1Mls
involves: 129/Sv * C57BL/6 * FVB/N * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
endocrine/exocrine glands
• ovariectomized female mice exposed to estrogen exhibit a 2-fold increase in ductal thickening and extensive side-branching compared to similarly treated wild-type mice (J:147439)
• estrogen-induced secondary branching is 3- to 4-fold greater and tertiary branching 5- to 7-fold greater than in similarly treated wild-type mice (J:147439)
• female mice exposed to high levels of estrogen develop abnormal mammary lesions or focal dysplasia unlike similarly treated wild-type mice with a 4-fold increase in lesion frequency and a 2.5-fold increase in lesion diameter (J:147439)

tumorigenesis
• estrogen-treated mice develop ductal carcinoma in situ in the mammary glands unlike similarly treated wild-type mice
• estrogen-treated lesions exhibit nuclear atypia and heterogeneity, complete filling of ductal lumens, and local infiltration with small blood vessels
• ductal lesions in estrogen-treated mice exhibit abnormal distribution of myoepithelial cells, increased cell proliferation at terminal end buds, stromal activation, and enriched in mammary stem/progenitor cells
• ductal lesions in estrogen treated mice express Npm1 (B23), a marker for tamoxifen resistance, and Nol3 (Arc), a marker of resistance to apoptosis

integument
• ovariectomized female mice exposed to estrogen exhibit a 2-fold increase in ductal thickening and extensive side-branching compared to similarly treated wild-type mice (J:147439)
• estrogen-induced secondary branching is 3- to 4-fold greater and tertiary branching 5- to 7-fold greater than in similarly treated wild-type mice (J:147439)
• female mice exposed to high levels of estrogen develop abnormal mammary lesions or focal dysplasia unlike similarly treated wild-type mice with a 4-fold increase in lesion frequency and a 2.5-fold increase in lesion diameter (J:147439)

Mouse Models of Human Disease
OMIM IDRef(s)
Breast Cancer 114480 J:147439


Mouse Genome Informatics
hm5
    Cav1tm1Mls/Cav1tm1Mls
involves: 129/Sv * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Cav1tm1Mls/Cav1tm1Mls mice show lung abnormalities, with thickened alveolar septa and hypercellularity

mortality/aging
• mutants exhibit a decrease in survival (7 days vs. 13 days in wild-type) when challenged with Salmonella enterica serovar Typhimurium
• 50% reduction in life span, with viability declining between 27 and 65 weeks of age
• mice that die within this time frame, die suddenly, without any visible signs of disease

respiratory system
• reactive endothelial cell proliferation
• hyperemic lungs
• alveolar spaces are filled with extravasated red blood cells
• increase in inflammatory infiltrates in the lung
• parenchymal hypercellularity

cardiovascular system
• reactive endothelial cell proliferation
• myocardium is thickened in both the left and right ventricles at 12 months of age
• myocyte hypertrophy and disorganization
• increase in intraventricular septal thickness during diastole
• 12 month old mutants exhibit concentric left ventricular hypertrophy
• the right ventricular chamber is about 70% and 25% larger than in wild-type at 4 and 12 months of age, respectively
• about 18% and 36% increase in left ventricular wall thickness at 4 and 12 months of age, respectively
• increase in fibrosis at 12 months of age
• hyperemic lungs
• alveolar spaces are filled with extravasated red blood cells
• impaired response to phenylephrine (PE) due to increased Nos3 activity
• impaired acetylcholine induced relaxation of the aortic rings
• 29% decrease in fractional shortening at 12 months of age, indicating reduction in left ventricular systolic fraction
• severe right-sided heart failure

cellular
• adipocytes from peri-gonadal white adipose tissue show barren membrane architecture indicating a loss of caveolae (J:75192)
• endothelial cells lack caveolae membranes (J:75193)
• uptake and transport of albumin from the blood to the interstitium by endothelial cells is defective due to absence of caveolae

homeostasis/metabolism
N
• plasma glucose, insulin, and cholesterol levels were similar to wild-type in both fasting and post-prandial states at 12 weeks of age, standard chow diet (J:75192)
• mutants do not exhibit significant changes in paremeters of energy expenditure such as VO2, VCO2, respiratory quotient, heat release, or movement, indicating that leanness is not due to increased energy expenditure (J:75192)
• exercise intolerance when compared to wild-type in a swimming test
• transvascular protein transport is increased, with mutants showing higher albumin and IgM clearance from the plasma to peritoneium, and increased clearance of high molecular weight Ficoll
• mutants are resistant to obesity when challenged with a high fat diet for 36 weeks
• plasma ACRP30 (an adipoctye secreted factor) levels are reduced by 8-10 fold
• plasma leptin levels are reduced more than 2-fold
• lungs exhibit increased NOS3 (eNOS)-derived nitric oxide production and impaired NOS2 (iNOS)-derived nitric oxide production after LPS challenge
• mutants show kinetically delayed clearance of triglycerides in an oral fat tolerance test
• free fatty acids levels fail to undergo the expected post-eating reduction seen in wild-type
• triglyceride levels are elevated in the fasted state and increased even more post-prandially, due to perturbed lipoprotein lipase activity
• the chylomicron/VLDL fraction of triglycerides is increased during fasting and increases dramatically above wild-type mice in the post-prandial state
• increased production of interferon-gamma at 3 days post Salmonella infection
• increased production of IL-6 at 3 days post Salmonella infection
• increased production of TNF-alpha at 3 days post Salmonella infection
• increased production of the chemokines CCL3, CXCL10 and CXCL10 at 3 days post Salmonella infection
• mutants are more susceptible to DMBA (7,12-dimethylbenzanthracene)-induced skin carcinogenesis
• 100% of mice develop tumors at 12 weeks of age compared to 10% of wild-type mice
• tumor multiplicity is greatly increased
• mutants exhibit an increase of cerebral volume of infarction compared to wild-type, with fewer numbers of proliferating endothelial cells and increased numbers of cells undergoing apoptotic cell death in ischemic brains

muscle
• myocyte hypertrophy and disorganization
• impaired response to phenylephrine (PE) due to increased Nos3 activity
• impaired acetylcholine induced relaxation of the aortic rings
• 29% decrease in fractional shortening at 12 months of age, indicating reduction in left ventricular systolic fraction
• skeletal muscle fibers of males exhibit and increase in tubular aggregate formation with age
• sarcoplasmic reticulum is dilated in skeletal muscle of males

endocrine/exocrine glands
• size of mammary glands is reduced, however overall architecture is intact (J:75192)
• the number of mammary ducts per field is increased (J:75192)
• the mammary ductal epithelia exhibits hyperproliferation (J:75192)
• intraductal hyperplasia, with the epithelial cell layer 3-4 cells thick (J:109251)
• mammary epithelial cell hyperplasia, even in 6 week old virgin mice (J:109251)
• mammary epithelial cell hyperplasia, even in 6 week old virgin mice (J:109251)

tumorigenesis
N
• mice fail to spontaneously develop mammary tumors, even at up to 9 months of age, although mammary glands at this age show pronounced lobular development with numerous acini per terminal ductal lobular unit, hyperplasia of the mammary epithelial lining, and fibrosis (J:109251)
• mutants are more susceptible to DMBA (7,12-dimethylbenzanthracene)-induced skin carcinogenesis
• 100% of mice develop tumors at 12 weeks of age compared to 10% of wild-type mice
• tumor multiplicity is greatly increased

immune system
• marrow cultures from mutants generate about 20% more osteoclasts than wild-type cultures
• polymorphonuclear neutrophil (PMN) sequestration in lungs is reduced in mutants compared to wild-type after LPS challenge
• mutants lack infiltration of white pulp by neutrophils when infected with Salmonella
• macrophages exhibit increased inflammatory responses and increased nitric oxide production in vitro in response to Salmonella LPS
• macrophages show no differences in the uptake of opsonized bacteria from wild-type
• increased production of interferon-gamma at 3 days post Salmonella infection
• increased production of IL-6 at 3 days post Salmonella infection
• increased production of TNF-alpha at 3 days post Salmonella infection
• increased production of the chemokines CCL3, CXCL10 and CXCL10 at 3 days post Salmonella infection
• mutants show reduced mortality compared to wild-type mice following LPS challenge due to elevated nitric oxide as mutants treated with an NOS3 inhibitor show 100% mortality
• lungs are protected from LPS-induced lung injury, showing no increase in lung microvascular permeability or edema formation as in wild-type mice
• adhesion of wild-type PMN to mutant endothelial cells is reduced after LPS challenge
• increase in inflammatory infiltrates in the lung
• mutants exhibit increased production of inflammatory cytokines, chemokines, and nitric oxide in response to Salmonella infection but are unable to control the systemic infection and have higher bacterial burden in spleen and liver
• mutants exhibit a decrease in survival (7 days vs. 13 days in wild-type) when challenged with Salmonella enterica serovar Typhimurium

nervous system
• mutants exhibit an increase of cerebral volume of infarction compared to wild-type, with fewer numbers of proliferating endothelial cells and increased numbers of cells undergoing apoptotic cell death in ischemic brains

hematopoietic system
• marrow cultures from mutants generate about 20% more osteoclasts than wild-type cultures
• polymorphonuclear neutrophil (PMN) sequestration in lungs is reduced in mutants compared to wild-type after LPS challenge
• mutants lack infiltration of white pulp by neutrophils when infected with Salmonella
• macrophages exhibit increased inflammatory responses and increased nitric oxide production in vitro in response to Salmonella LPS
• macrophages show no differences in the uptake of opsonized bacteria from wild-type

skeleton
• marrow cultures from mutants generate about 20% more osteoclasts than wild-type cultures
• 58.4% increase in ephiphyseal bone volume at 5 weeks
• 77.4 % increase in metaphyseal bone volume at 8 weeks but not at 5 weeks of age
• 33% increase in stiffness and 33% decrease in postyield deflection of cortical bone
• at the femoral mid-diaphysis, the total cortical area is increased by 19.7% and 13.8%, at 5 and 8 weeks of age, respectively, with expanded periosteal and endocortical surfaces at 8 weeks
• metaphyseal trabeculae are greater in number and show reduced spacing, however trabecular thickness is not different from wild-typ
• increase in trabecular number in the distal femoral epiphysis
• increase in thickness of the distal femoral epiphysis
• mineral apposition rate is increased at both metaphyseal and cortical sites at 5 weeks of age and regresses by 8 weeks of age
• increase in bone formation rate at the trabecular and cortical sites at 5 weeks of age
• stiffer bone capable of bearing a greater load before failure
• 25% increase in maximum force

adipose tissue
• mutants on a high fat diet exhibit hyperplastic brown adipose tissue, putatively secondary to elevated triglyceride levels
• the hypodermal fat layer is absent in both males and females at 12 weeks of age
• underdeveloped subcutaneous fat pads
• at 36 weeks of age on a high fat diet, subcutaneous fat is severely perturbed in females, with reduced numbers of adipoctyes that are heterogeneous in size and marked interstitial fibrosis and hypercellularity
• at 12 weeks of age on a high fat diet, mutants exhibit a 2-fold reduction in female mammary gland/subcutaneous WAT
• 2-fold reduction in the fat-to-water ratio
• at 35 weeks of age on a high fat diet, mutants only show minor gains in fat mass compared to wild-type and have dramatically reduced adiposity in all fat pads compared to wild-type
• at 12 weeks of age, female mammary gland 4/subcutaneous adipocytes contain reduced lipid droplets
• lipid droplet size in adipoctyes is about 2-3-fold smaller than in wild-type
• lipid droplet size in adipoctyes is about 2-3-fold smaller than in wild-type
• underdeveloped peri-gonadal fat pads
• at 36 weeks of age on a high fat diet, mammary gland 4 fat is severely perturbed in females, with reduced numbers of adipoctyes that are heterogeneous in size and marked interstitial fibrosis and hypercellularity (J:75192)

behavior/neurological
• daily food intake is higher in females (J:75192)
• exercise intolerance when compared to wild-type in a swimming test

growth/size
• 2-fold reduction in the fat-to-water ratio
• at 35 weeks of age on a high fat diet, mutants only show minor gains in fat mass compared to wild-type and have dramatically reduced adiposity in all fat pads compared to wild-type
• mice are leaner than wild-type mice on a chow diet
• relative decrease in weight is exacerbated on a high fat diet
• resistance to diet-induced obesity due to an inability to convert lipoprotein triglycerides into the fat droplet storage form
• lack of weight gain
• mutants are resistant to obesity when challenged with a high fat diet for 36 weeks

liver/biliary system
N
• livers show no increase in weight or steatosis (J:75192)

integument
• the hypodermal fat layer is absent in both males and females at 12 weeks of age
• underdeveloped subcutaneous fat pads
• at 36 weeks of age on a high fat diet, subcutaneous fat is severely perturbed in females, with reduced numbers of adipoctyes that are heterogeneous in size and marked interstitial fibrosis and hypercellularity
• size of mammary glands is reduced, however overall architecture is intact (J:75192)
• the number of mammary ducts per field is increased (J:75192)
• the mammary ductal epithelia exhibits hyperproliferation (J:75192)
• intraductal hyperplasia, with the epithelial cell layer 3-4 cells thick (J:109251)
• mammary epithelial cell hyperplasia, even in 6 week old virgin mice (J:109251)
• mammary epithelial cell hyperplasia, even in 6 week old virgin mice (J:109251)
• mutants develop extensive epidermal hyperplasia in response to DMBA treatment before tumor formation


Mouse Genome Informatics
hm6
    Cav1tm1Mls/Cav1tm1Mls
involves: 129/Sv * C57BL/6J * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• a defect in insulin-regulated lipogenesis contributes to the lean phenotype

homeostasis/metabolism
• ligation of the common carotid artery causes a significant increase in neointimal lesion formation compared to wild-type mice
• mouse embryonic fibroblasts (MEFs) and macrophages under normal conditions or loaded with cholesterol contain reduced free cholesterol but increased esterified-cholesterol content
• however, when cholesterol loaded, macrophages show an increase in total cellular cholesterol content
• cellular cholesterol efflux not affected although ABCA1-mediated cholesterol efflux is more sensitive to the inhibitory effects of glyburide in macrophages
• post-prandial serum levels of insulin were increased in mice that had been on a high fat diet for 9 months
• interstitial cells of Cajal and smooth muscles of the intestine (longitudinal muscles) show reduced responsiveness to endogenous and exogenous nitric oxide
• N-omega-nitro-L-arginine is ineffective to inhibit intestinal relaxation and exogenous nitric oxide donor sodium nitroprusside relaxes longitudinal muscle less than in controls
• apamin significantly reduces small intestinal tissue relaxation to electrical field stimulation in nonadrenergic noncholinergic conditions in mutants but not controls indicating that the normal spontaneous contraction of intestinal muscle is probably maintained by increased activity of apamin-sensitive mediators
• mutants show a blunted decline in glucose levels upon insulin injection
• serum nonesterified fatty acid levels fail to rise in mutants in response to prolonged fasting
• mutants exhibit a 5-fold reduction in their lipolytic response to a beta3-specific adrenergic receptor agonist
• mutants show a slower wound healing rate when circular punch biopsies are done on the back skin compared to wild-type

cardiovascular system
• lung capillaries exhibit smaller tight junctions and abnormalities in capillary endothelial cell adhesion to the basement membrane
• large increase in microvascular permeability as indicated by an increased rate of clearance for iodinated serum albumin from the circulatory system and lower levels of endogenous serum albumin
• paracellular movement of Ruthenium Red is increased in lung endothelial cells indicating hyperpermeable tight junctions/capillaries
• treatment with L-NAME, a nitric-oxide synthasae inhibitor, restores normal microvascular permeability
• at pressures between 30 and 70 mmHg, cerebral arteries develop less myogenic tone than wild-type, indicating attenuated pressure-induced constriction
• pressure induces a smaller depolarization and smaller arterial wall intracellular calcium elevation in mutant cerebral arteries than in wild-type, resulting in reduced myogenic constriction
• membrane depolarization induced by 60 mM potassium results in attenuated arterial wall intracellular calcium elevation and constriction in cerebral arteries
• N-omega-nitro-L-arginine, a nitric oxide synthase inhibitor, does not restore myogenic tone in cerebral arteries, indicating that NOS activation and nitric oxide generation do not significantly contribute to the attenuated myogenic response
• ligation of the common carotid artery causes a significant increase in neointimal lesion formation compared to wild-type mice

adipose tissue
• perigonadal adipocytes completely lack an electron-dense thick band of material that surrounds the normal lipid droplet

cellular
• mouse embryonic fibroblasts (MEFs) lose polarity when plated on fibronectin, exhibiting a round shape with aberrant actin cytoskeleton architecture
• microtubule organizing center reorientation toward the leading edge of a wound is reduced in MEFs
• protrusive and retractile activities at cell edges are higher in MEFs and protrusions and retractions occurs throughout the cell perimeter instead of protrusions in the direction of movement and retractions in the rear end as in wild-type MEFs
• caveolae are absent in the longitudinal muscles of the intestine (J:114334)
• absence of caveolae in vascular smooth muscle cells (J:115492)
• chondrocytes lack caveolae (J:128103)
• MEFs plated on fibronectin move faster and exhibit impaired directional migration compared to wild-type MEFs
• wound closure and chemotactic response of MEFs in a transwell assay are impaired
• mouse embryonic fibroblasts (MEFs) and macrophages under normal conditions or loaded with cholesterol contain reduced free cholesterol but increased esterified-cholesterol content
• however, when cholesterol loaded, macrophages show an increase in total cellular cholesterol content
• cellular cholesterol efflux not affected although ABCA1-mediated cholesterol efflux is more sensitive to the inhibitory effects of glyburide in macrophages

skeleton
• metaphyseal bone volume is greater
• increase in number of trabeculae in metaphyseal bone
• at 8 weeks of age, in the metaphysis the trabeculae are coated with a thin layer of bone
• increase in number of trabeculae in metaphyseal bone
• at 8 weeks of age, in the metaphysis the trabeculae are coated with a thin layer of bone
• cartilage of the costochondral junction is more cellular
• at 8 weeks of age, cartilage extends into the epiphyseal bone and metaphyseal marrow
• increase in the number of columns of cells in the proliferating cell zone
• increase in the number of columns of cells in the hypertrophic cell zone of growth plates
• number of hypertrophic cells is increased for each column of cells
• tibial growth plates are 12.3% longer than in wild-type
• costochondral growth plates are longer
• growth plates of femoral chondyles are extended, both vertically and in cross-section
• hyaline cartilage is more cellular, extending distally from the rib
• growth zone chondrocytes fail to exhibit a response to 1,25-dihydroxyvitaminD3

behavior/neurological
• exploratory behavior in a new environment is reduced as early as 13 weeks of age
• mutants exhibit spinning upon tail suspension; frequency and intensity of spinning increases progressively with age such that by 50 weeks, it is seen in 50% of mutants and in all mutants by 80-90 weeks of age
• exhibit clasping as early as 20 weeks of age and the number of mutants that clasp increases with age
• mutants exhibit impaired ability to hold and maneuver on a bar
• mutants tend to stop and/or change direction of movement while traversing a tunnel more often than controls
• mutants are less active than their wild-type littermates
• wider overlap (distance between superimposed hindpaw and forepaw) that coincides with stride abnormalities
• evident by 10 weeks of age

nervous system
• brains are smaller at 60 weeks of age but not at 11 weeks of age
• the internal capsule fiber bundles are smaller in size in the striatum

digestive/alimentary system
• mutants exhibit impaired small intestinal nitric oxide function

muscle
• at pressures between 30 and 70 mmHg, cerebral arteries develop less myogenic tone than wild-type, indicating attenuated pressure-induced constriction
• pressure induces a smaller depolarization and smaller arterial wall intracellular calcium elevation in mutant cerebral arteries than in wild-type, resulting in reduced myogenic constriction
• membrane depolarization induced by 60 mM potassium results in attenuated arterial wall intracellular calcium elevation and constriction in cerebral arteries
• N-omega-nitro-L-arginine, a nitric oxide synthase inhibitor, does not restore myogenic tone in cerebral arteries, indicating that NOS activation and nitric oxide generation do not significantly contribute to the attenuated myogenic response


Mouse Genome Informatics
hm7
    Cav1tm1Mls/Cav1tm1Mls
Not Specified
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• 20-25% reduction in cerebrovascular volume is observed in the hippocampi from young mice
• amyloid beta production is increased in the hippocampus of young mice
• young (3-6 months) mice exhibit a reduction in the number of neurons in the CA1 region
• young mice exhibit areas of potential plaque development and disorganized astrocytes
• Fluoro-Jade B and Nissl staining of the CA1 region from 12 month old mice indicates increased neuronal degeneration as compared to age-matched controls
• young (3-6 months) mice exhibit a reduction in the number of neurons within the dentate gyrus
• increase in glia and glial scar formation within the dentate gyrus
• Fluoro-Jade B and Nissl staining of the CA1 region from 12 month old mice indicates increased neuronal degeneration as compared to age-matched controls
• tau deposits are elevated in hippocampal homogenates from young mice
• increase in glia and glial scar formation within the dentate gyrus
• astrocytes in young mice are disorganized as compared to young wild-type mice
• young mice exhibit a significant reduction in hippocampal synapses in comparison to age-matched wild-type mice, but similar to aged wild-type mice
• cytoskeletal architecture within dendrites is unorganized
• young mice subjected to ischemic preconditioning prior to lethal ischemia lack the ability to protect CA1 neurons, a phenomenon observed in aged wild-type mice

cardiovascular system
• 20-25% reduction in cerebrovascular volume is observed in the hippocampi from young mice

homeostasis/metabolism
• amyloid beta production is increased in the hippocampus of young mice

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:168335


Mouse Genome Informatics
hm8
    Cav1tm1Mls/Cav1tm1Mls
STOCK Cav1tm1Mls/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
endocrine/exocrine glands
• more than a 4-fold increase in thyrocyte proliferation, however mice do not develop a goiter because there is an increase in thyrocyte apoptosis

cardiovascular system
• phenylephrine causes vascular contraction that is significantly reduced compared to wild-type on a high salt diet, however when the phenylephrine contraction is presented as a percentage of maximum and the ED50 is calculated, there is no significant difference
• vascular contraction in response to membrane depolarization by high KCl is reduced in mutants compared to wild-type mice on a high salt diet
• acetylcholine causes enhanced aortic relaxation compared to wild-type on a high salt and low salt diet
• mice on a high salt diet treated with N-G-nitro-L-arginine methyl ester (L-NAME) exhibit a more elevated blood pressure than similarly treated wild-type mice, however no differences are seen on a low salt diet

growth/size
• total body weight is reduced in mutants compared to wild-type on both high salt and low salt diets

muscle
• phenylephrine causes vascular contraction that is significantly reduced compared to wild-type on a high salt diet, however when the phenylephrine contraction is presented as a percentage of maximum and the ED50 is calculated, there is no significant difference
• vascular contraction in response to membrane depolarization by high KCl is reduced in mutants compared to wild-type mice on a high salt diet
• acetylcholine causes enhanced aortic relaxation compared to wild-type on a high salt and low salt diet


Mouse Genome Informatics
cx9
    Apoetm1Unc/Apoetm1Unc
Cav1tm1Mls/Cav1tm1Mls

involves: 129/Sv * 129P2/OlaHsd * C57BL/6J * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• 70% reduction in atherosclerotic lesion area, indicating protection against the development of aortic atheromas

homeostasis/metabolism
• 1.3 to 1.5-fold increase in non-HDL plasma cholesterol levels when fed a normal or high-fat diet
• on a normal or high-fat diet
• on a normal or high-fat diet
• approximate 2.3-fold increase in plasma triglyceride when fed a normal or high-fat diet


Mouse Genome Informatics
cx10
    Cav1tm1Mls/Cav1tm1Mls
Cdkn2atm1Rdp/Cdkn2atm1Rdp

involves: 129/Sv * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
• MEFs exhibit an increase in the S-phase fraction and a decrease in the G0/G1 fraction, indicating an arrest in the G0/G1 phase
• MEFs exhibit increased hyperproliferation compared to single Cdkn2a homozygous MEFs

endocrine/exocrine glands
• fibrosis of the mammary gland epithelial duct (J:90334)
• increase in ductal wall thickness (J:90334)
• increase in side-branching of the mammary gland epithelial duct (J:90334)
• hyperplasia of the mammary gland epithelial duct (J:90334)

integument
• fibrosis of the mammary gland epithelial duct (J:90334)
• increase in ductal wall thickness (J:90334)
• increase in side-branching of the mammary gland epithelial duct (J:90334)
• hyperplasia of the mammary gland epithelial duct (J:90334)


Mouse Genome Informatics
cx11
    Cav1tm1Mls/Cav1tm1Mls
Tg(TRAMP)8247Ng/0

involves: 129/Sv * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• development of primary prostate tumor growth is significantly impeded in mutants in comparison to Tg(TRAMP)8247Ng hemizygous mice (J:133066)
• development of regional and distant metastasis is attenuated (J:133066)
• tumors derived from mutants exhibit an increase in apoptotic cells compared to cells in Tg(TRAMP)8247Ng hemizygous mice (J:133066)


Mouse Genome Informatics
cx12
    Cav1tm1Mls/Cav1tm1Mls
Tg(MMTV-PyVT)634Mul/0

involves: 129/Sv * C57BL/6J * FVB/N * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• development of mulifocal dysplastic mammary lesions is accelerated compared to single hemizygous Tg(MMTV-PyVT)634Mul mice; 2-fold increase in the number of lesions and 5-6-fold increase in the total area occupied by the lesions at 3 weeks of age


Mouse Genome Informatics
cx13
    Cav1tm1Mls/Cav1+
Tg(MMTV-PyVT)634Mul/0

involves: 129/Sv * C57BL/6J * FVB/N * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• mutants develop dysplastic mammary lesions to a similar extent as observed in single hemizygous Tg(MMTV-PyVT)634Mul mice


Mouse Genome Informatics
cx14
    Cav1tm1Mls/Cav1tm1Mls
Cav3tm1Mls/Cav3tm1Mls

involves: 129/Sv * C57BL/6J * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
• double homozygotes are viable and fertile but lack morphologically identifiable caveolae in endothelia, adipocytes, smooth muscle cells, skeletal muscle fibers, and cardiac myocytes (first "truly caveolae-deficient" mouse model)
• in addition, double homozygotes are deficient in all three caveolin gene family members (first "caveolin-less" mouse model)

cardiovascular system
• at 2 months, double homozygotes display significant cardiac myocyte hypertrophy and disarray interspaced with areas of myocytolysis
• at 2 months of age, double homozygotes exhibit a ~34% increase in interventricular septal thickness relative to wild-type mice
• at 2 months, double homozygotes show a ~33% increase in heart to body weight ratios relative to wild-type mice
• at 2 months, double homozygotes display concentric cardiac hypertrophy, with increases of ~34% in interventricular septal thickness, posterior wall thickness, and left ventricular wall thickness; no further changes are noted at 4 months
• at 2 months, double homozygotes exhibit significant left ventricular hypertrophy relative to wild-type mice; no further hypertrophy is noted at 4 months
• left ventricular hypertrophy is associated with a switch to fetal programming, as shown by anomalous up-regulation of atrial natriuretic peptide
• at 2 months, double homozygotes show significant left ventricular dilation relative to wild-type mice, as shown by increases in end-diastolic diameter (3.27 0.16 vs 2.71 0.13 mm) and end-systolic diameter (2.02 0.07 vs 1.12 0.13 mm); no further dilation is noted at 4 months
• at 2 months, double homozygotes show a ~41% increase in left ventricular wall thickness relative to wild-type mice; a notable increase is also detected in right ventricular wall thickness
• in double homozygotes, the increase in left ventricular wall thickness exceeds that observed in either single homozygote, suggesting a synergistic effect
• at 2 months, double homozygotes show cardiac interstitial fibrosis
• at 2 months, double homozygotes show a significant reduction in left ventricular fractional shortening relative to wild-type mice (38.33 2.57 vs. 58.65 5.48 mm); however, no further deterioration is noted at 4 months
• neither significant differences in heart rate nor obvious conduction defects or cardiac arrhythmias are observed
• double homozygotes develop a severe cardiomyopathy with left ventricular hypertrophy and chamber dilation, as assessed by gross morphology, cardiac MRI, and transthoracic echocardiography
• at 2 months, double homozygotes exhibit significant chronic cardiac inflammation characterized by increased cellular infiltrates and fibrosis

muscle
• at 2 months, double homozygotes display significant cardiac myocyte hypertrophy and disarray interspaced with areas of myocytolysis
• at 2 months, double homozygotes show a significant reduction in left ventricular fractional shortening relative to wild-type mice (38.33 2.57 vs. 58.65 5.48 mm); however, no further deterioration is noted at 4 months
• neither significant differences in heart rate nor obvious conduction defects or cardiac arrhythmias are observed
• double homozygotes develop a severe cardiomyopathy with left ventricular hypertrophy and chamber dilation, as assessed by gross morphology, cardiac MRI, and transthoracic echocardiography

immune system
• at 2 months, double homozygotes exhibit significant chronic cardiac inflammation characterized by increased cellular infiltrates and fibrosis