Phenotypes associated with this allele

• Allele Symbol: Cav1^tm1Mls
• Allele Name: targeted mutation 1, Michael P Lisanti
• Allele ID: MGI:2180364
• Summary: 14 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cav1^tm1Mls/Cav1^tm1Mls	B6.Cg-Cav1^tm1Mls	MGI:4417870
hm2	Cav1^tm1Mls/Cav1^tm1Mls	B6.Cg-Cav1^tm1Mls/J	MGI:4420453
hm3	Cav1^tm1Mls/Cav1^tm1Mls	FVB.Cg-Cav1^tm1Mls	MGI:5316848
hm4	Cav1^tm1Mls/Cav1^tm1Mls	involves: 129/Sv * C57BL/6 * FVB/N * SJL	MGI:3843497
hm5	Cav1^tm1Mls/Cav1^tm1Mls	involves: 129/Sv * C57BL/6J * SJL	MGI:2669819
hm6	Cav1^tm1Mls/Cav1^tm1Mls	involves: 129/Sv * C57BL/6 * SJL	MGI:2669401
hm7	Cav1^tm1Mls/Cav1^tm1Mls	Not Specified	MGI:5014041
hm8	Cav1^tm1Mls/Cav1^tm1Mls	STOCK Cav1^tm1Mls/J	MGI:4420233
cx9	Apoe^tm1Unc/Apoe^tm1Unc Cav1^tm1Mls/Cav1^tm1Mls	involves: 129/Sv * 129P2/OlaHsd * C57BL/6J * SJL	MGI:4418046
cx10	Cav1^tm1Mls/Cav1^+ Tg(MMTV-PyVT)634Mul/0	involves: 129/Sv * C57BL/6J * FVB/N * SJL	MGI:4417966
cx11	Cav1^tm1Mls/Cav1^tm1Mls Tg(MMTV-PyVT)634Mul/0	involves: 129/Sv * C57BL/6J * FVB/N * SJL	MGI:4417965
cx12	Cav1^tm1Mls/Cav1^tm1Mls Cav3^tm1Mls/Cav3^tm1Mls	involves: 129/Sv * C57BL/6J * SJL	MGI:3625731
cx13	Cav1^tm1Mls/Cav1^tm1Mls Cdkn2a^tm1Rdp/Cdkn2a^tm1Rdp	involves: 129/Sv * C57BL/6 * SJL	MGI:4418482
cx14	Cav1^tm1Mls/Cav1^tm1Mls Tg(TRAMP)8247Ng/0	involves: 129/Sv * C57BL/6 * SJL	MGI:4418492

Genotype
MGI:4417870

hm1

• Allelic Composition: Cav1^tm1Mls/Cav1^tm1Mls
• Genetic Background: B6.Cg-Cav1^tm1Mls

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

endocrine/exocrine glands

abnormal mammary gland growth during pregnancy ( J:120010 )

♀ • premature development of the lobuloalveolar compartment of the mammary gland during pregnancy

♀ • however, serum prolactin levels are normal

abnormal lactation ( 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

reproductive system

abnormal mammary gland growth during pregnancy ( J:120010 )

♀ • premature development of the lobuloalveolar compartment of the mammary gland during pregnancy

♀ • however, serum prolactin levels are normal

adipose tissue

abnormal fat cell morphology ( J:205741 )

• adipocytes lack caveolae

abnormal brown fat cell morphology ( J:105133 )

• mitochodria of brown adipocytes are larger and dilated and much less electron dense than mitochondria of wild-type mice

increased brown fat cell lipid droplet size ( J:105133 )

• adipocytes of brown adipose tissue contain larger lipid droplets than in wild-type mice

homeostasis/metabolism

impaired adaptive thermogenesis ( J:105133 )

• 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

decreased core body temperature ( J:105133 )

• mild, but significant, decrease in resting core body temperature

decreased fatty acids level ( J:105133 )

• mutants fail to exhibit the normal increase in serum nonesterifited fatty acids induced by fasting or fasting/cold treatment

abnormal triglyceride level ( J:105133 )

• 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

impaired lipolysis ( J:105133 )

• 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

abnormal mammary gland growth during pregnancy ( J:120010 )

♀ • premature development of the lobuloalveolar compartment of the mammary gland during pregnancy

♀ • however, serum prolactin levels are normal

abnormal lactation ( 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

cardiovascular system

abnormal vascular endothelial cell morphology ( J:205741 )

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

abnormal lung vasculature morphology ( J:205741 )

• gaps in the lung capillary

cellular

absent caveolae ( J:205741 )

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

respiratory system

abnormal lung vasculature morphology ( J:205741 )

• gaps in the lung capillary

Genotype
MGI:4420453

hm2

• Allelic Composition: Cav1^tm1Mls/Cav1^tm1Mls
• Genetic Background: B6.Cg-Cav1^tm1Mls/J

cellular

absent caveolae ( J:143600 )

reproductive system

reduced fertility ( J:143600 )

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

respiratory system

abnormal lung morphology ( J:143600 )

• 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

pulmonary edema ( J:143600 )

• presence of vascular-derived fluid in pulmonary tissues

abnormal pulmonary elastic fiber morphology ( J:143600 )

• 60% increase in elastic fiber deposits in the lungs, with thicker layers of elastic fibers primarily around airways and arteries

increased lung elastance ( J:143600 )

• from 3 months on, mutants exhibit a a sustained increase in lung elastance

abnormal respiratory mechanics ( J:143600 )

• from 3 months on, mutants exhibit altered respiratory mechanics, suggesting stiffening of the lung tissue

increased airway resistance ( J:143600 )

• from 3 months on, mutants exhibit an increase in airway resistance

decreased lung compliance ( J:143600 )

• from 3 months on, mutants exhibit a decrease in lung compliance

homeostasis/metabolism

pulmonary edema ( J:143600 )

• presence of vascular-derived fluid in pulmonary tissues

cardiovascular system

increased vascular permeability ( J:143600 )

• 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

Genotype
MGI:5316848

hm3

• Allelic Composition: Cav1^tm1Mls/Cav1^tm1Mls
• Genetic Background: FVB.Cg-Cav1^tm1Mls

homeostasis/metabolism

abnormal homeostasis ( J:182288 )

• increase in lactate levels following 3-mercaptopicolinic acid treatment

• elevated circulating peroxide levels and a small decrease in circulating pyruvate levels

decreased susceptibility to diet-induced obesity ( J:182288 )

• when placed on a high fat diet

abnormal circulating amino acid level ( J:182288 )

• elevated circulating branched-chain amino acid levels

increased blood urea nitrogen level ( J:182288 )

increased circulating glycerol level ( J:182288 )

• following 3-mercaptopicolinic acid treatment

increased oxygen consumption ( J:182288 )

abnormal respiratory quotient ( J:182288 )

• variability in the respiratory exchange ratio over a 24 hour period is reduced

increased respiratory quotient ( J:182288 )

abnormal glucose homeostasis ( J:182288 )

• 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

hyperglycemia ( J:182288 )

• upon refeeding display fairly severe hyperglycemia

increased circulating insulin level ( J:182288 )

enhanced gluconeogenesis ( J:182288 )

• 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

decreased liver glycogen level ( J:182288 )

• in the fed state

increased liver glycogen level ( J:182288 )

• in moderately fasted mice

insulin resistance ( J:182288 )

decreased circulating adiponectin level ( J:182288 )

• reduced total circulating levels and a decrease in the proportion of the HMW form

abnormal free fatty acids level ( J:182288 )

• delay in suppression of free fatty acid levels following refeeding

• impaired beta3-AR agonist induced release of free fatty acids

increased triglyceride level ( J:182288 )

• in fed and fasted mice

enhanced lipolysis ( J:182288 )

cellular

abnormal cellular respiration ( J:182288 )

• MEFs display a preference for glycolysis in glucose-deprived media

abnormal respiratory electron transport chain ( J:182288 )

• 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

decreased total body fat amount ( J:182288 )

• reduced fat mass

abnormal adipose tissue physiology ( J:182288 )

• enhanced uptake of leucine in mildly fasted mice

growth/size/body

weight loss ( J:182288 )

• lose more weight when fasted

decreased susceptibility to diet-induced obesity ( J:182288 )

• when placed on a high fat diet

increased liver weight ( J:182288 )

• under all conditions tested

behavior/neurological

increased food intake ( J:182288 )

muscle

abnormal skeletal muscle morphology ( J:182288 )

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

liver/biliary system

increased liver weight ( J:182288 )

• under all conditions tested

decreased liver glycogen level ( J:182288 )

• in the fed state

increased liver glycogen level ( J:182288 )

• in moderately fasted mice

decreased susceptibility to diet-induced hepatic steatosis ( J:182288 )

• fasting induced and high fat diet induced hepatic steatosis are reduced

abnormal liver physiology ( J:182288 )

• alternate day fasting has no effect of hepatic lipid content unlike in wild-type mice

• hepatic triglyceride synthesis appears to be reduced

Genotype
MGI:3843497

hm4

• Allelic Composition: Cav1^tm1Mls/Cav1^tm1Mls
• Genetic Background: involves: 129/Sv * C57BL/6 * FVB/N * SJL

endocrine/exocrine glands

abnormal mammary gland morphology ( J:147439 )

♀ • 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

♀ • 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

♀ • 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

increased mammary gland tumor incidence ( J:147439 )

• 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

neoplasm

increased mammary gland tumor incidence ( J:147439 )

• 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

abnormal mammary gland morphology ( J:147439 )

♀ • 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

♀ • 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

♀ • 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

increased mammary gland tumor incidence ( J:147439 )

• 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

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
breast cancer		DOID:1612	OMIM:114480	J:147439

Genotype
MGI:2669819

hm5

• Allelic Composition: Cav1^tm1Mls/Cav1^tm1Mls
• Genetic Background: involves: 129/Sv * C57BL/6J * SJL

growth/size/body

decreased body weight ( J:84260 )

• a defect in insulin-regulated lipogenesis contributes to the lean phenotype

homeostasis/metabolism

abnormal vascular wound healing ( J:115492 )

• ligation of the common carotid artery causes a significant increase in neointimal lesion formation compared to wild-type mice

abnormal cellular cholesterol metabolism ( J:116292 )

• 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

increased circulating insulin level ( J:84260 )

• post-prandial serum levels of insulin were increased in mice that had been on a high fat diet for 9 months

abnormal nitric oxide homeostasis ( J:114334 )

• 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

insulin resistance ( J:84260 )

• mutants show a blunted decline in glucose levels upon insulin injection

impaired lipolysis ( J:89326 )

• 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

impaired wound healing ( J:134719 )

• mutants show a slower wound healing rate when circular punch biopsies are done on the back skin compared to wild-type

cardiovascular system

abnormal vascular endothelial cell morphology ( J:79595 )

• lung capillaries exhibit smaller tight junctions and abnormalities in capillary endothelial cell adhesion to the basement membrane

increased vascular permeability ( J:79595 )

• 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

decreased vasoconstriction ( J:120603 )

• 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

abnormal vascular wound healing ( J:115492 )

• ligation of the common carotid artery causes a significant increase in neointimal lesion formation compared to wild-type mice

adipose tissue

abnormal fat cell morphology ( J:89326 )

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

cellular

abnormal cell morphology ( J:134719 )

• 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

abnormal actin cytoskeleton morphology ( J:134719 )

• mouse embryonic fibroblasts (MEFs) lose polarity when plated on fibronectin, exhibiting a round shape with aberrant actin cytoskeleton architecture

abnormal microtubule organizing center morphology ( J:134719 )

• microtubule organizing center reorientation toward the leading edge of a wound is reduced in MEFs

absent caveolae ( J:114334 , J:115492 , J:128103 )

• 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)

abnormal fibroblast chemotaxis ( J:134719 )

• MEFs plated on fibronectin move faster and exhibit impaired directional migration compared to wild-type MEFs

decreased fibroblast chemotaxis ( J:134719 )

• wound closure and chemotactic response of MEFs in a transwell assay are impaired

abnormal cellular cholesterol metabolism ( J:116292 )

• 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

abnormal long bone epiphyseal plate morphology ( J:128103 )

• at 8 weeks of age, cartilage extends into the epiphyseal bone and metaphyseal marrow

abnormal long bone epiphyseal plate proliferative zone ( J:128103 )

• increase in the number of columns of cells in the proliferating cell zone

abnormal long bone hypertrophic chondrocyte zone ( J:128103 )

• 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

increased long bone epiphyseal plate size ( J:128103 )

• 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

abnormal long bone metaphysis morphology ( J:128103 )

• 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

abnormal costochondral joint morphology ( J:128103 )

• cartilage of the costochondral junction is more cellular

abnormal trabecular bone morphology ( J:128103 )

• 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

abnormal hyaline cartilage morphology ( J:128103 )

• hyaline cartilage is more cellular, extending distally from the rib

abnormal chondrocyte physiology ( J:128103 )

• growth zone chondrocytes fail to exhibit a response to 1,25-dihydroxyvitaminD3

behavior/neurological

decreased exploration in new environment ( J:110712 )

• exploratory behavior in a new environment is reduced as early as 13 weeks of age

abnormal involuntary movement ( J:110712 )

• 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

limb grasping ( J:110712 )

• exhibit clasping as early as 20 weeks of age and the number of mutants that clasp increases with age

decreased grip strength ( J:110712 )

• mutants exhibit impaired ability to hold and maneuver on a bar

abnormal locomotor behavior ( J:110712 )

• mutants tend to stop and/or change direction of movement while traversing a tunnel more often than controls

abnormal gait ( J:110712 )

• wider overlap (distance between superimposed hindpaw and forepaw) that coincides with stride abnormalities

short stride length ( J:110712 )

• evident by 10 weeks of age

decreased locomotor activity ( J:110712 )

• mutants are less active than their wild-type littermates

nervous system

decreased brain size ( J:110712 )

• brains are smaller at 60 weeks of age but not at 11 weeks of age

decreased brain weight ( J:110712 )

abnormal brain internal capsule morphology ( J:110712 )

• the internal capsule fiber bundles are smaller in size in the striatum

digestive/alimentary system

abnormal digestive system physiology ( J:114334 )

• mutants exhibit impaired small intestinal nitric oxide function

muscle

decreased vasoconstriction ( J:120603 )

• 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

Genotype
MGI:2669401

hm6

• Allelic Composition: Cav1^tm1Mls/Cav1^tm1Mls
• Genetic Background: involves: 129/Sv * C57BL/6 * SJL

Cav1^tm1Mls/Cav1^tm1Mls mice show lung abnormalities, with thickened alveolar septa and hypercellularity

mortality/aging

increased susceptibility to bacterial infection induced morbidity/mortality ( J:115914 )

• mutants exhibit a decrease in survival (7 days vs. 13 days in wild-type) when challenged with Salmonella enterica serovar Typhimurium

premature death ( J:87282 )

• 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

abnormal pulmonary endothelial cell surface ( J:87282 )

• reactive endothelial cell proliferation

pulmonary hyperemia ( J:87282 )

• hyperemic lungs

• alveolar spaces are filled with extravasated red blood cells

lung inflammation ( J:87282 )

• increase in inflammatory infiltrates in the lung

thick pulmonary interalveolar septum ( J:75193 , J:87282 )

abnormal pulmonary alveolar parenchyma morphology ( J:75193 )

• parenchymal hypercellularity

cardiovascular system

abnormal pulmonary endothelial cell surface ( J:87282 )

• reactive endothelial cell proliferation

abnormal myocardium layer morphology ( J:87282 )

• myocardium is thickened in both the left and right ventricles at 12 months of age

myocardial fiber disarray ( J:87282 )

• myocyte hypertrophy and disorganization

thick interventricular septum ( J:87282 )

• increase in intraventricular septal thickness during diastole

cardiac hypertrophy ( J:87282 )

• 12 month old mice show thickening of the myocardium in both ventricles and generalized myocyte hypertrophy

heart left ventricle hypertrophy ( J:87282 )

• 12 month old mutants exhibit concentric left ventricular hypertrophy

increased heart left ventricle wall thickness ( J:87282 )

• about 18% and 36% increase in left ventricular wall thickness at 4 and 12 months of age, respectively

dilated heart right ventricle ( J:87282 )

• the right ventricular chamber is about 70% and 25% larger than in wild-type at 4 and 12 months of age, respectively

cardiac fibrosis ( J:87282 )

• increase in fibrosis at 12 months of age

pulmonary hyperemia ( J:87282 )

• hyperemic lungs

• alveolar spaces are filled with extravasated red blood cells

decreased cardiac muscle contractility ( J:87282 )

• 29% decrease in fractional shortening at 12 months of age, indicating reduction in left ventricular systolic fraction

pulmonary hypertension ( J:87282 )

abnormal vasoconstriction ( J:75193 )

• impaired response to phenylephrine (PE) due to increased Nos3 activity

abnormal vasodilation ( J:75193 )

• impaired acetylcholine induced relaxation of the aortic rings

congestive heart failure ( J:87282 )

• severe right-sided heart failure

cellular

absent caveolae ( J:73489 , J:75192 , J:75193 )

• 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)

abnormal vesicle-mediated transport ( J:73489 )

• uptake and transport of albumin from the blood to the interstitium by endothelial cells is defective due to absence of caveolae

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:75192 )

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

N • 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

impaired exercise endurance ( J:75193 )

• exercise intolerance when compared to wild-type in a swimming test

abnormal homeostasis ( J:116286 )

• 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

decreased susceptibility to diet-induced obesity ( J:75192 )

• mutants are resistant to obesity when challenged with a high fat diet for 36 weeks

abnormal blood homeostasis ( J:75192 )

• plasma ACRP30 (an adipocyte secreted factor) levels are reduced by 8-10 fold

decreased circulating leptin level ( J:75192 )

• plasma leptin levels are reduced more than 2-fold

abnormal nitric oxide homeostasis ( J:139304 )

• lungs exhibit increased NOS3 (eNOS)-derived nitric oxide production and impaired NOS2 (iNOS)-derived nitric oxide production after LPS challenge

abnormal lipid homeostasis ( J:75192 )

• mutants show kinetically delayed clearance of triglycerides in an oral fat tolerance test

abnormal circulating free fatty acids level ( J:75192 )

• free fatty acids levels fail to undergo the expected post-eating reduction seen in wild-type

increased circulating triglyceride level ( J:75192 )

• triglyceride levels are elevated in the fasted state and increased even more post-prandially, due to perturbed lipoprotein lipase activity

increased circulating VLDL triglyceride level ( J:75192 )

• the chylomicron/VLDL fraction of triglycerides is increased during fasting and increases dramatically above wild-type mice in the post-prandial state

abnormal cytokine level ( J:115914 )

increased circulating CXCL10 level ( J:115914 )

• increased production of CXCL10 at 3 days post Salmonella infection

increased circulating interferon-gamma level ( J:115914 )

• increased production of interferon-gamma at 3 days post Salmonella infection

increased circulating interleukin-6 level ( J:115914 )

• increased production of IL-6 at 3 days post Salmonella infection

increased circulating tumor necrosis factor level ( J:115914 )

• increased production of TNF-alpha at 3 days post Salmonella infection

increased incidence of tumors by chemical induction ( J:83485 )

• 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

increased cerebral infarct size ( J:133702 )

• 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

abnormal myocardium layer morphology ( J:87282 )

• myocardium is thickened in both the left and right ventricles at 12 months of age

myocardial fiber disarray ( J:87282 )

• myocyte hypertrophy and disorganization

heart left ventricle hypertrophy ( J:87282 )

• 12 month old mutants exhibit concentric left ventricular hypertrophy

decreased cardiac muscle contractility ( J:87282 )

• 29% decrease in fractional shortening at 12 months of age, indicating reduction in left ventricular systolic fraction

abnormal vasoconstriction ( J:75193 )

• impaired response to phenylephrine (PE) due to increased Nos3 activity

abnormal vasodilation ( J:75193 )

• impaired acetylcholine induced relaxation of the aortic rings

abnormal skeletal muscle fiber morphology ( J:117199 )

• 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

abnormal mammary gland morphology ( J:75192 )

♀ • size of mammary glands is reduced, however overall architecture is intact

abnormal mammary gland epithelium morphology ( J:109251 )

♀ • mammary epithelial cell hyperplasia, even in 6 week old virgin mice

abnormal mammary gland duct morphology ( J:75192 )

♀ • the number of mammary ducts per field is increased

♀ • the mammary ductal epithelia exhibits hyperproliferation

mammary gland duct hyperplasia ( J:109251 )

♀ • intraductal hyperplasia, with the epithelial cell layer 3-4 cells thick

mammary gland hyperplasia ( J:109251 )

♀ • mammary epithelial cell hyperplasia, even in 6 week old virgin mice

neoplasm

neoplasm ( J:109251 )

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

increased incidence of tumors by chemical induction ( J:83485 )

• 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

abnormal osteoclast morphology ( J:141361 )

• marrow cultures from mutants generate about 20% more osteoclasts than wild-type cultures

abnormal neutrophil physiology ( J:139304 )

• polymorphonuclear neutrophil (PMN) sequestration in lungs is reduced in mutants compared to wild-type after LPS challenge

impaired neutrophil recruitment ( J:115914 )

• mutants lack infiltration of white pulp by neutrophils when infected with Salmonella

abnormal macrophage physiology ( J:115914 )

• 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

abnormal cytokine level ( J:115914 )

increased circulating CXCL10 level ( J:115914 )

• increased production of CXCL10 at 3 days post Salmonella infection

increased circulating interferon-gamma level ( J:115914 )

• increased production of interferon-gamma at 3 days post Salmonella infection

increased circulating interleukin-6 level ( J:115914 )

• increased production of IL-6 at 3 days post Salmonella infection

increased circulating tumor necrosis factor level ( J:115914 )

• increased production of TNF-alpha at 3 days post Salmonella infection

abnormal chemokine secretion ( J:115914 )

• increased production of the chemokines CCL3, CXCL1 and CXCL10 at 3 days post Salmonella infection

decreased susceptibility to endotoxin shock ( J:139304 )

• 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

lung inflammation ( J:87282 )

• increase in inflammatory infiltrates in the lung

increased susceptibility to bacterial infection ( J:115914 )

• 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

increased susceptibility to bacterial infection induced morbidity/mortality ( J:115914 )

• mutants exhibit a decrease in survival (7 days vs. 13 days in wild-type) when challenged with Salmonella enterica serovar Typhimurium

nervous system

increased cerebral infarct size ( J:133702 )

• 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

abnormal osteoclast morphology ( J:141361 )

• marrow cultures from mutants generate about 20% more osteoclasts than wild-type cultures

abnormal neutrophil physiology ( J:139304 )

• polymorphonuclear neutrophil (PMN) sequestration in lungs is reduced in mutants compared to wild-type after LPS challenge

impaired neutrophil recruitment ( J:115914 )

• mutants lack infiltration of white pulp by neutrophils when infected with Salmonella

abnormal macrophage physiology ( J:115914 )

• 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

abnormal osteoclast morphology ( J:141361 )

• marrow cultures from mutants generate about 20% more osteoclasts than wild-type cultures

abnormal long bone epiphysis morphology ( J:141361 )

• 58.4% increase in ephiphyseal bone volume at 5 weeks

abnormal long bone metaphysis morphology ( J:141361 )

• 77.4 % increase in metaphyseal bone volume at 8 weeks but not at 5 weeks of age

abnormal compact bone morphology ( J:141361 )

• 33% increase in stiffness and 33% decrease in postyield deflection of cortical bone

increased femoral compact bone area ( J:141361 )

• 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

abnormal bone trabecula morphology ( J:141361 )

• metaphyseal trabeculae are greater in number and show reduced spacing, however trabecular thickness is not different from wild-typ

increased bone trabecula number ( J:141361 )

• increase in trabecular number in the distal femoral epiphysis

increased trabecular bone thickness ( J:141361 )

• increase in thickness of the distal femoral epiphysis

abnormal bone mineralization ( J:141361 )

• mineral apposition rate is increased at both metaphyseal and cortical sites at 5 weeks of age and regresses by 8 weeks of age

premature bone ossification ( J:141361 )

• increase in bone formation rate at the trabecular and cortical sites at 5 weeks of age

increased bone strength ( J:141361 )

• stiffer bone capable of bearing a greater load before failure

• 25% increase in maximum force

adipose tissue

increased brown adipose tissue amount ( J:75192 )

• mutants on a high fat diet exhibit hyperplastic brown adipose tissue, putatively secondary to elevated triglyceride levels

absent subcutaneous adipose tissue ( J:75192 )

• the hypodermal fat layer is absent in both males and females at 12 weeks of age

decreased subcutaneous adipose tissue amount ( J:75192 )

• 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

decreased white adipose tissue amount ( J:75192 )

• at 12 weeks of age on a high fat diet, mutants exhibit a 2-fold reduction in female mammary gland/subcutaneous WAT

decreased total body fat amount ( J:75192 )

• 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

abnormal fat cell morphology ( J:75192 )

• 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

decreased white fat cell lipid droplet size ( J:75192 )

• lipid droplet size in adipoctyes is about 2-3-fold smaller than in wild-type

abnormal gonadal fat pad morphology ( J:75192 )

• underdeveloped peri-gonadal fat pads

abnormal mammary fat pad morphology ( J:75192 )

♀ • 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

behavior/neurological

increased food intake ( J:75192 )

♀ • daily food intake is higher in females

impaired exercise endurance ( J:75193 )

• exercise intolerance when compared to wild-type in a swimming test

growth/size/body

cardiac hypertrophy ( J:87282 )

• 12 month old mice show thickening of the myocardium in both ventricles and generalized myocyte hypertrophy

heart left ventricle hypertrophy ( J:87282 )

• 12 month old mutants exhibit concentric left ventricular hypertrophy

decreased body weight ( J:75192 )

• 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

slow postnatal weight gain ( J:75192 )

• lack of weight gain

decreased susceptibility to diet-induced obesity ( J:75192 )

• mutants are resistant to obesity when challenged with a high fat diet for 36 weeks

liver/biliary system

liver/biliary system phenotype ( J:75192 )

N • livers show no increase in weight or steatosis

integument

absent subcutaneous adipose tissue ( J:75192 )

• the hypodermal fat layer is absent in both males and females at 12 weeks of age

decreased subcutaneous adipose tissue amount ( J:75192 )

• 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

abnormal mammary gland morphology ( J:75192 )

♀ • size of mammary glands is reduced, however overall architecture is intact

abnormal mammary gland epithelium morphology ( J:109251 )

♀ • mammary epithelial cell hyperplasia, even in 6 week old virgin mice

abnormal mammary gland duct morphology ( J:75192 )

♀ • the number of mammary ducts per field is increased

♀ • the mammary ductal epithelia exhibits hyperproliferation

mammary gland duct hyperplasia ( J:109251 )

♀ • intraductal hyperplasia, with the epithelial cell layer 3-4 cells thick

mammary gland hyperplasia ( J:109251 )

♀ • mammary epithelial cell hyperplasia, even in 6 week old virgin mice

epidermal hyperplasia ( J:83485 )

• mutants develop extensive epidermal hyperplasia in response to DMBA treatment before tumor formation

limbs/digits/tail

increased femoral compact bone area ( J:141361 )

• 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

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hypertrophic cardiomyopathy		DOID:11984		J:87282

Genotype
MGI:5014041

hm7

• Allelic Composition: Cav1^tm1Mls/Cav1^tm1Mls
• Genetic Background: Not Specified

nervous system

abnormal brain vasculature morphology ( J:168335 )

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

amyloid beta deposits ( J:168335 )

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

abnormal hippocampus CA1 region morphology ( J:168335 )

• 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

abnormal dentate gyrus morphology ( J:168335 )

• 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

hippocampal neuron degeneration ( J:168335 )

• 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 protein deposits ( J:168335 )

• tau deposits are elevated in hippocampal homogenates from young mice

abnormal CNS glial cell morphology ( J:168335 )

• increase in glia and glial scar formation within the dentate gyrus

abnormal astrocyte morphology ( J:168335 )

• astrocytes in young mice are disorganized as compared to young wild-type mice

astrocytosis ( J:168335 )

decreased CNS synapse formation ( J:168335 )

• young mice exhibit a significant reduction in hippocampal synapses in comparison to age-matched wild-type mice, but similar to aged wild-type mice

abnormal dendrite morphology ( J:168335 )

• cytoskeletal architecture within dendrites is unorganized

brain ischemia ( J:168335 )

• 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

abnormal brain vasculature morphology ( J:168335 )

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

homeostasis/metabolism

amyloid beta deposits ( J:168335 )

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

cellular

abnormal cell cytoskeleton morphology ( J:168335 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Alzheimer's disease		DOID:10652		J:168335

Genotype
MGI:4420233

hm8

• Allelic Composition: Cav1^tm1Mls/Cav1^tm1Mls
• Genetic Background: STOCK Cav1^tm1Mls/J

endocrine/exocrine glands

abnormal thyroid follicular cell morphology ( J:119709 )

• 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

increased systemic arterial blood pressure ( J:132392 )

• 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

decreased vasoconstriction ( J:132392 )

• 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

increased vasodilation ( J:132392 )

• acetylcholine causes enhanced aortic relaxation compared to wild-type on a high salt and low salt diet

growth/size/body

decreased body weight ( J:132392 )

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

muscle

decreased vasoconstriction ( J:132392 )

• 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

increased vasodilation ( J:132392 )

• acetylcholine causes enhanced aortic relaxation compared to wild-type on a high salt and low salt diet

Genotype
MGI:4418046

cx9

• Allelic Composition: Apoe^tm1Unc/Apoe^tm1Unc; Cav1^tm1Mls/Cav1^tm1Mls
• Genetic Background: involves: 129/Sv * 129P2/OlaHsd * C57BL/6J * SJL

cardiovascular system

decreased susceptibility to atherosclerosis ( J:101788 )

• 70% reduction in atherosclerotic lesion area, indicating protection against the development of aortic atheromas

homeostasis/metabolism

increased circulating cholesterol level ( J:101788 )

• 1.3 to 1.5-fold increase in non-HDL plasma cholesterol levels when fed a normal or high-fat diet

increased circulating LDL cholesterol level ( J:101788 )

• on a normal or high-fat diet

increased circulating VLDL cholesterol level ( J:101788 )

• on a normal or high-fat diet

increased circulating triglyceride level ( J:101788 )

• approximate 2.3-fold increase in plasma triglyceride when fed a normal or high-fat diet

Genotype
MGI:4417966

cx10

• Allelic Composition: Cav1^tm1Mls/Cav1⁺; Tg(MMTV-PyVT)634Mul/0
• Genetic Background: involves: 129/Sv * C57BL/6J * FVB/N * SJL

neoplasm

increased mammary gland tumor incidence ( J:132472 )

• mutants develop dysplastic mammary lesions to a similar extent as observed in single hemizygous Tg(MMTV-PyVT)634Mul mice

integument

increased mammary gland tumor incidence ( J:132472 )

• mutants develop dysplastic mammary lesions to a similar extent as observed in single hemizygous Tg(MMTV-PyVT)634Mul mice

endocrine/exocrine glands

increased mammary gland tumor incidence ( J:132472 )

• mutants develop dysplastic mammary lesions to a similar extent as observed in single hemizygous Tg(MMTV-PyVT)634Mul mice

Genotype
MGI:4417965

cx11

• Allelic Composition: Cav1^tm1Mls/Cav1^tm1Mls; Tg(MMTV-PyVT)634Mul/0
• Genetic Background: involves: 129/Sv * C57BL/6J * FVB/N * SJL

neoplasm

increased mammary gland tumor incidence ( J:132472 )

• 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

endocrine/exocrine glands

increased mammary gland tumor incidence ( J:132472 )

• 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

integument

increased mammary gland tumor incidence ( J:132472 )

• 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

Genotype
MGI:3625731

cx12

• Allelic Composition: Cav1^tm1Mls/Cav1^tm1Mls; Cav3^tm1Mls/Cav3^tm1Mls
• Genetic Background: involves: 129/Sv * C57BL/6J * SJL

cellular

cardiac interstitial fibrosis ( J:77372 )

• at 2 months, double homozygotes show cardiac interstitial fibrosis

absent caveolae ( J:77372 )

• 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)

growth/size/body

increased heart weight ( J:77372 )

• at 2 months, double homozygotes show a ~33% increase in heart to body weight ratios relative to wild-type mice

cardiac hypertrophy ( J:77372 )

• 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

heart left ventricle hypertrophy ( J:77372 )

• 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

cardiovascular system

abnormal myocardial fiber morphology ( J:77372 )

• at 2 months, double homozygotes display significant cardiac myocyte hypertrophy and disarray interspaced with areas of myocytolysis

myocardial fiber disarray ( J:77372 )

thick interventricular septum ( J:77372 )

• at 2 months of age, double homozygotes exhibit a ~34% increase in interventricular septal thickness relative to wild-type mice

increased heart weight ( J:77372 )

• at 2 months, double homozygotes show a ~33% increase in heart to body weight ratios relative to wild-type mice

cardiac hypertrophy ( J:77372 )

• 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

heart left ventricle hypertrophy ( J:77372 )

• 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

increased heart left ventricle wall thickness ( J:77372 )

• at 2 months, double homozygotes show a ~41% increase in left ventricular wall thickness relative to wild-type mice

• increase in left ventricular wall thickness exceeds that observed in either single homozygote, suggesting a synergistic effect

dilated heart left ventricle ( J:77372 )

• 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

increased heart right ventricle wall thickness ( J:77372 )

• at 2 months, a notable increase is detected in right ventricular wall thickness

cardiac interstitial fibrosis ( J:77372 )

• at 2 months, double homozygotes show cardiac interstitial fibrosis

decreased heart left ventricle muscle contractility ( J:77372 )

• 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

cardiomyopathy ( J:77372 )

• double homozygotes develop a severe cardiomyopathy with left ventricular hypertrophy and chamber dilation, as assessed by gross morphology, cardiac MRI, and transthoracic echocardiography

heart inflammation ( J:77372 )

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

muscle

abnormal myocardial fiber morphology ( J:77372 )

• at 2 months, double homozygotes display significant cardiac myocyte hypertrophy and disarray interspaced with areas of myocytolysis

myocardial fiber disarray ( J:77372 )

heart left ventricle hypertrophy ( J:77372 )

• 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

decreased heart left ventricle muscle contractility ( J:77372 )

• 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

cardiomyopathy ( J:77372 )

• 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

heart inflammation ( J:77372 )

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

Genotype
MGI:4418482

cx13

• Allelic Composition: Cav1^tm1Mls/Cav1^tm1Mls; Cdkn2a^tm1Rdp/Cdkn2a^tm1Rdp
• Genetic Background: involves: 129/Sv * C57BL/6 * SJL

cellular

abnormal cell cycle ( J:90334 )

• 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

increased fibroblast proliferation ( J:90334 )

• MEFs exhibit increased hyperproliferation compared to single Cdkn2a homozygous MEFs

endocrine/exocrine glands

abnormal mammary gland duct morphology ( J:90334 )

♀ • fibrosis of the mammary gland epithelial duct

♀ • increase in ductal wall thickness

abnormal branching of the mammary ductal tree ( J:90334 )

♀ • increase in side-branching of the mammary gland epithelial duct

mammary gland duct hyperplasia ( J:90334 )

♀ • hyperplasia of the mammary gland epithelial duct

integument

abnormal mammary gland duct morphology ( J:90334 )

♀ • fibrosis of the mammary gland epithelial duct

♀ • increase in ductal wall thickness

abnormal branching of the mammary ductal tree ( J:90334 )

♀ • increase in side-branching of the mammary gland epithelial duct

mammary gland duct hyperplasia ( J:90334 )

♀ • hyperplasia of the mammary gland epithelial duct

Genotype
MGI:4418492

cx14

• Allelic Composition: Cav1^tm1Mls/Cav1^tm1Mls; Tg(TRAMP)8247Ng/0
• Genetic Background: involves: 129/Sv * C57BL/6 * SJL

neoplasm

decreased tumor incidence ( J:133066 )

♂ • development of primary prostate tumor growth is significantly impeded in mutants in comparison to Tg(TRAMP)8247Ng hemizygous mice

♂ • development of regional and distant metastasis is attenuated

♂ • tumors derived from mutants exhibit an increase in apoptotic cells compared to cells in Tg(TRAMP)8247Ng hemizygous mice