Phenotypes associated with this allele

• Allele Symbol: Cbl^tm1Ddlb
• Allele Name: targeted mutation 1, David D L Bowtell
• Allele ID: MGI:2180578
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cbl^tm1Ddlb/Cbl^tm1Ddlb	involves: 129S1/Sv	MGI:3623282
hm2	Cbl^tm1Ddlb/Cbl^tm1Ddlb	involves: 129S1/Sv * C57BL/6	MGI:3623283
hm3	Cbl^tm1Ddlb/Cbl^tm1Ddlb	involves: 129S1/Sv * C57BL/6J	MGI:3623281
ht4	Cbl^tm1Ddlb/Cbl^+	involves: 129S1/Sv * C57BL/6	MGI:3623292
ht5	Cbl^tm1Ddlb/Cbl^tm2Wlan	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:3623285
ht6	Cbl^tm1Ddlb/Cbl^tm2Wlan	involves: 129S1/Sv * C57BL/6	MGI:3711320

Genotype
MGI:3623282

hm1

• Allelic Composition: Cbl^tm1Ddlb/Cbl^tm1Ddlb
• Genetic Background: involves: 129S1/Sv

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

hematopoietic system

enlarged spleen ( J:81965 )

• about a 80% increase in spleen size

spleen hyperplasia ( J:81965 )

• increase in the number of megakaryocytes, megakaryoblasts, and myelocytes mostly located in clusters towards the spleen periphery

abnormal myeloblast morphology/development ( J:81965 )

• expansion of cells in the myeloid lineage in the bone marrow

• increase in the proportion of ITGAM and LY6G expressing cells and decrease in the proportion of B220+ cells

increased spleen red pulp amount ( J:81965 )

• expanded red pulp resulting in darker spleen color

abnormal T cell physiology ( J:81965 )

• CD5 and CD69 expression (markers of T cell activation) are increased in DP thymocytes

immune system

enlarged spleen ( J:81965 )

• about a 80% increase in spleen size

spleen hyperplasia ( J:81965 )

• increase in the number of megakaryocytes, megakaryoblasts, and myelocytes mostly located in clusters towards the spleen periphery

increased spleen red pulp amount ( J:81965 )

• expanded red pulp resulting in darker spleen color

abnormal T cell physiology ( J:81965 )

• CD5 and CD69 expression (markers of T cell activation) are increased in DP thymocytes

growth/size/body

enlarged spleen ( J:81965 )

• about a 80% increase in spleen size

spleen hyperplasia ( J:81965 )

• increase in the number of megakaryocytes, megakaryoblasts, and myelocytes mostly located in clusters towards the spleen periphery

Genotype
MGI:3623283

hm2

• Allelic Composition: Cbl^tm1Ddlb/Cbl^tm1Ddlb
• Genetic Background: involves: 129S1/Sv * C57BL/6

hematopoietic system

enlarged spleen ( J:103366 )

• spleen is enlarged about 1.2- to 2-fold compared to wild-type mice due to expansion of the red pulp

spleen hyperplasia ( J:103366 )

• increase in the number of megakaryocytes, megakaryoblasts, and myelocytes but no increase in the number of lymphocytes is seen in the spleen

increased spleen red pulp amount ( J:103366 )

• expanded

adipose tissue

decreased total body fat amount ( J:94416 )

• despite increased caloric intake, a 40-50% decrease in the size of the adipose tissue depots (including both white and brown fat) is seen

• this phenotype is more pronounced in males than in females

abnormal fat cell morphology ( J:94416 )

• adipocyte volume is reduced by about 64% compared to wild-type mice

growth/size/body

increased lean body mass ( J:94416 )

• balances the decrease in adipose tissue resulting in no significant difference in total body weight

enlarged spleen ( J:103366 )

• spleen is enlarged about 1.2- to 2-fold compared to wild-type mice due to expansion of the red pulp

spleen hyperplasia ( J:103366 )

• increase in the number of megakaryocytes, megakaryoblasts, and myelocytes but no increase in the number of lymphocytes is seen in the spleen

behavior/neurological

polyphagia ( J:94416 )

increased locomotor activity ( J:94416 )

• about a 4-fold increase in ambulatory activity is seen, especially during the dark phase

homeostasis/metabolism

decreased circulating leptin level ( J:94416 )

• leptin levels are decreased by 66%; however adiponectin levels are similar to wild-type

increased body temperature ( J:94416 )

• rectal temperature is increased by 1 degree C independent of time of day or if the mice are fed or fasted overnight

• however, circulating levels of triiodothyronine or thyroxine are similar to wild-type in both the fed and fasted states

abnormal gas homeostasis ( J:94416 )

increased oxygen consumption ( J:94416 )

• whole body oxygen consumption corrected for the difference in lean mass is increased by 22% compared to wild-type mice

decreased respiratory quotient ( J:94416 )

• reduced respiratory quotient

abnormal glucose homeostasis ( J:94416 )

decreased circulating insulin level ( J:94416 )

• after an overnight fast insulin levels are decreased relative to wild-type but glucose levels are similar to wild-type

improved glucose tolerance ( J:94416 )

• improved glucose tolerance despite decreased insulin levels throughout the test

increased insulin sensitivity ( J:94416 )

abnormal lipid homeostasis ( J:94416 )

decreased circulating free fatty acids level ( J:94416 )

decreased liver triglyceride level ( J:94416 )

• triglyceride levels in the liver are decreased but those in the quadriceps muscle are similar to wild-type

muscle

abnormal muscle physiology ( J:94416 )

• glucose clearance in to glycogen is increased in the soleus and extensor digitorum longus muscles but not in the liver

increased skeletal muscle cell glucose uptake ( J:94416 )

• glucose uptake into skeletal muscle is increased about 2-fold; however glucose uptake into white and brown adipose tissue is not different from wild-type

• basal and insulin-stimulated glucose uptake are increased in soleus muscle explants by 65% and 30%, respectively; however, glucose uptake is not increased in fat explants

• basal, but not insulin-stimulated, glucose uptake is increased by 30% in extensor digitorum longus muscle explants

cellular

increased mitochondrial size ( J:94416 )

• a 2-fold increase in the average size of subsarcolemmal mitochondria is seen; however, no increase in mitochondrial area or cristae density is seen in the subsarcolemmal region

increased skeletal muscle cell glucose uptake ( J:94416 )

• glucose uptake into skeletal muscle is increased about 2-fold; however glucose uptake into white and brown adipose tissue is not different from wild-type

• basal and insulin-stimulated glucose uptake are increased in soleus muscle explants by 65% and 30%, respectively; however, glucose uptake is not increased in fat explants

• basal, but not insulin-stimulated, glucose uptake is increased by 30% in extensor digitorum longus muscle explants

immune system

enlarged spleen ( J:103366 )

• spleen is enlarged about 1.2- to 2-fold compared to wild-type mice due to expansion of the red pulp

spleen hyperplasia ( J:103366 )

• increase in the number of megakaryocytes, megakaryoblasts, and myelocytes but no increase in the number of lymphocytes is seen in the spleen

increased spleen red pulp amount ( J:103366 )

• expanded

liver/biliary system

decreased liver triglyceride level ( J:94416 )

• triglyceride levels in the liver are decreased but those in the quadriceps muscle are similar to wild-type

Genotype
MGI:3623281

hm3

• Allelic Composition: Cbl^tm1Ddlb/Cbl^tm1Ddlb
• Genetic Background: involves: 129S1/Sv * C57BL/6J

hematopoietic system

abnormal thymus cell ratio ( J:76895 )

• thymocyte numbers are increased at 5 - 5.5 weeks of age but is similar to wild-type at 7 - 9 weeks of age

• at 7 to 9 weeks of age the proportion of TCRB and CD3E expressing thymocytes is increased

extramedullary hematopoiesis ( J:76895 )

• extensive extramedullary hematopoiesis with large numbers of megakaryocytes and normoblasts is seen in the liver and spleen from birth

• however, bone marrow total cellularity and colony forming units are similar to wild-type

abnormal bone marrow cell morphology/development ( J:76895 )

• in some mice the proportion of IgM+ IgD- cells is increased

thrombocytosis ( J:76895 )

• platelet count is increased but erythrocyte, leukocyte, and reticulocyte numbers in the blood and packed cell volume are similar to wild-type

abnormal spleen morphology ( J:76895 )

• splenic fibrosis

enlarged spleen ( J:76895 )

abnormal splenic cell ratio ( J:76895 )

• in some mice the proportion of IgM+ IgD- cells is increased

immune system

abnormal thymus cell ratio ( J:76895 )

• thymocyte numbers are increased at 5 - 5.5 weeks of age but is similar to wild-type at 7 - 9 weeks of age

• at 7 to 9 weeks of age the proportion of TCRB and CD3E expressing thymocytes is increased

abnormal spleen morphology ( J:76895 )

• splenic fibrosis

enlarged spleen ( J:76895 )

abnormal splenic cell ratio ( J:76895 )

• in some mice the proportion of IgM+ IgD- cells is increased

abnormal lymph node cell ratio ( J:76895 )

• increased numbers of B and T cells

enlarged lymph nodes ( J:76895 )

adipose tissue

abnormal mammary fat pad morphology ( J:76895 )

• the mammary fat pads of virgin adult females are slightly thickened

skeleton

skeleton phenotype ( J:76895 )

N • long bone architecture and osteoclast numbers and morphology are normal

endocrine/exocrine glands

abnormal thymus cell ratio ( J:76895 )

• thymocyte numbers are increased at 5 - 5.5 weeks of age but is similar to wild-type at 7 - 9 weeks of age

• at 7 to 9 weeks of age the proportion of TCRB and CD3E expressing thymocytes is increased

abnormal branching of the mammary ductal tree ( J:76895 )

♀ • increased branching and density of ducts in virgin adult females

♀ • however, males and females are fertile and produce normal sized litters

integument

abnormal branching of the mammary ductal tree ( J:76895 )

♀ • increased branching and density of ducts in virgin adult females

♀ • however, males and females are fertile and produce normal sized litters

growth/size/body

enlarged spleen ( J:76895 )

Genotype
MGI:3623292

ht4

• Allelic Composition: Cbl^tm1Ddlb/Cbl⁺
• Genetic Background: involves: 129S1/Sv * C57BL/6

growth/size/body

increased body weight ( J:121012 )

• after 4 weeks on a high-fat diet, male mice are on average 3.5 g heavier than male Cbl^tm1Wlan/ Cbl^tm1Ddlb littermates

increased susceptibility to diet-induced obesity ( J:121012 )

• on a high fat diet (60% of caloric intake from fat) for 4 weeks, male mice gain more weight (3.5 g) than Cbl^tm1Wlan/ Cbl^tm1Ddlb littermates (1.5g)

adipose tissue

decreased white adipose tissue amount ( J:94416 )

• 30% decrease in epididymal white fat mass compared to wild-type mice

homeostasis/metabolism

increased susceptibility to diet-induced obesity ( J:121012 )

• on a high fat diet (60% of caloric intake from fat) for 4 weeks, male mice gain more weight (3.5 g) than Cbl^tm1Wlan/ Cbl^tm1Ddlb littermates (1.5g)

improved glucose tolerance ( J:121012 )

• male mice show modestly enhanced glucose clearance relative to wild-type controls

Genotype
MGI:3623285

ht5

• Allelic Composition: Cbl^tm1Ddlb/Cbl^tm2Wlan
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

mortality/aging

prenatal lethality, incomplete penetrance ( J:103366 )

• fewer than expected mutant mice are found at birth (31.8% rather than the expected 50%) however neonatal mortality is similar to mice heterozygous for Cbl^tm1Ddlb alone

immune system

abnormal thymus morphology ( J:103366 )

abnormal thymus size ( J:103366 )

• progressive loss of the thymus as mice age beginning at 2 weeks of age

thymus hypoplasia ( J:103366 )

• by 40 weeks of age mice have less than 1% of the number of thymocytes seen in heterozygous controls

abnormal T cell differentiation ( J:103366 )

abnormal double-negative T cell morphology ( J:103366 )

• slight but significant increase in the proportion of double negative T cells

decreased single-positive T cell number ( J:103366 )

• about a 40% decrease in the proportion of single positive T cells

abnormal spleen morphology ( J:103366 )

enlarged spleen ( J:103366 )

• spleen is enlarged about 2.5- to 3.5-fold compared to wild-type mice due to expansion of the red pulp

spleen hyperplasia ( J:103366 )

• increase in the number of megakaryocytes, megakaryoblasts, and myelocytes but no increase in the number of lymphocytes is seen in the spleen

increased spleen red pulp amount ( J:103366 )

• expanded

abnormal splenic cell ratio ( J:103366 )

• the proportion of splenic T cells is reduced by about 80% compared to control littermates

abnormal T cell physiology ( J:103366 )

• cultured thymocytes are more sensitive to apoptosis induced by anti-CD3 antibodies alone

abnormal T cell activation ( J:103366 )

• a greater proportion of CD4+ T cells express higher levels of activation markers (CD44 and CD25) but the absolute numbers of these cells are decreased compared to mice heterozygous or homozygous for Cbl^tm1Ddlb alone

abnormal lymph node cell ratio ( J:103366 )

• lymph nodes contain 50% fewer CD4+ and CD8+ T cells and an increased proportion of B cells

pigmentation

increased ear pigmentation ( J:103366 )

• darker ears compared to both agouti and black wild-type mice

darkened coat color ( J:103366 )

• darker coat compared to both agouti and black wild-type mice

abnormal foot pigmentation ( J:103366 )

• darker feet compared to both agouti and black wild-type mice

increased tail pigmentation ( J:103366 )

• darker tails compared to both agouti and black wild-type mice

hematopoietic system

abnormal thymus morphology ( J:103366 )

abnormal thymus size ( J:103366 )

• progressive loss of the thymus as mice age beginning at 2 weeks of age

thymus hypoplasia ( J:103366 )

• by 40 weeks of age mice have less than 1% of the number of thymocytes seen in heterozygous controls

abnormal T cell differentiation ( J:103366 )

abnormal double-negative T cell morphology ( J:103366 )

• slight but significant increase in the proportion of double negative T cells

decreased single-positive T cell number ( J:103366 )

• about a 40% decrease in the proportion of single positive T cells

abnormal spleen morphology ( J:103366 )

enlarged spleen ( J:103366 )

• spleen is enlarged about 2.5- to 3.5-fold compared to wild-type mice due to expansion of the red pulp

spleen hyperplasia ( J:103366 )

• increase in the number of megakaryocytes, megakaryoblasts, and myelocytes but no increase in the number of lymphocytes is seen in the spleen

increased spleen red pulp amount ( J:103366 )

• expanded

abnormal splenic cell ratio ( J:103366 )

• the proportion of splenic T cells is reduced by about 80% compared to control littermates

abnormal T cell physiology ( J:103366 )

• cultured thymocytes are more sensitive to apoptosis induced by anti-CD3 antibodies alone

abnormal T cell activation ( J:103366 )

• a greater proportion of CD4+ T cells express higher levels of activation markers (CD44 and CD25) but the absolute numbers of these cells are decreased compared to mice heterozygous or homozygous for Cbl^tm1Ddlb alone

hearing/vestibular/ear

increased ear pigmentation ( J:103366 )

• darker ears compared to both agouti and black wild-type mice

craniofacial

increased ear pigmentation ( J:103366 )

• darker ears compared to both agouti and black wild-type mice

integument

increased ear pigmentation ( J:103366 )

• darker ears compared to both agouti and black wild-type mice

darkened coat color ( J:103366 )

• darker coat compared to both agouti and black wild-type mice

abnormal foot pigmentation ( J:103366 )

• darker feet compared to both agouti and black wild-type mice

increased tail pigmentation ( J:103366 )

• darker tails compared to both agouti and black wild-type mice

limbs/digits/tail

increased tail pigmentation ( J:103366 )

• darker tails compared to both agouti and black wild-type mice

endocrine/exocrine glands

abnormal thymus morphology ( J:103366 )

abnormal thymus size ( J:103366 )

• progressive loss of the thymus as mice age beginning at 2 weeks of age

thymus hypoplasia ( J:103366 )

• by 40 weeks of age mice have less than 1% of the number of thymocytes seen in heterozygous controls

growth/size/body

increased ear pigmentation ( J:103366 )

• darker ears compared to both agouti and black wild-type mice

enlarged spleen ( J:103366 )

• spleen is enlarged about 2.5- to 3.5-fold compared to wild-type mice due to expansion of the red pulp

spleen hyperplasia ( J:103366 )

• increase in the number of megakaryocytes, megakaryoblasts, and myelocytes but no increase in the number of lymphocytes is seen in the spleen

Genotype
MGI:3711320

ht6

• Allelic Composition: Cbl^tm1Ddlb/Cbl^tm2Wlan
• Genetic Background: involves: 129S1/Sv * C57BL/6

growth/size/body

decreased body weight ( J:121012 )

• mice weigh ~5% less than Cbl^tm1Ddlb heterozygous or wild-type male littermates at 18-24 weeks of age

decreased susceptibility to diet-induced obesity ( J:121012 )

adipose tissue

decreased brown adipose tissue amount ( J:121012 )

• brown fat mass is reduced ~20% relative to male Cbl^tm1Ddlb heterozygous littermates

decreased total body fat amount ( J:121012 )

• animals show ~25% reduction in fat mass compared to male Cbl^tm1Ddlb heterozygous or wild-type littermates

abnormal epididymal fat pad morphology ( J:121012 )

• epididymal fat mass is reduced ~33% compared with male Cbl^tm1Ddlb /+ heterozygous littermates

• high-fat fed mice have ~40% less epididymal fat mass than male Cbl^tm1Ddlb /+ heterozygous littermates

behavior/neurological

abnormal food intake ( J:121012 )

• mice have higher energy intake compared to male Cbl^tm1Ddlb /+ heterozygous littermates

homeostasis/metabolism

decreased susceptibility to diet-induced obesity ( J:121012 )

decreased circulating insulin level ( J:121012 )

• male mice show lower levels in fasted state and during the glucose tolerance test

• high-fat-fed male mice have ~45% lower circulating insulin levels than high-fat fed Cbl^tm1Ddlb /+ heterozygous littermates

decreased circulating leptin level ( J:121012 )

• levels are reduced ~55% (0.70 ng/ml vs 1.53 ng/ml in Cbl^tm1Ddlb /+ heterozygous littermates)

decreased circulating free fatty acids level ( J:121012 )

• levels are reduced ~20% (0.71 mmol/l vs 0.76 mmol/l in Cbl^tm1Ddlb /+ heterozygous littermates) at 18-24 weeks of age

decreased circulating triglyceride level ( J:121012 )

• levels are reduced relative to male Cbl^tm1Ddlb /+ heterozygous littermates (0.51 mmol/l vs 0.74 mmol/l)

increased oxygen consumption ( J:121012 )

• mice exhibit a 13% increase in whole body oxygen consumption compared to male Cbl^tm1Ddlb /+ heterozygous littermates)

• high-fat fed mice have ~10% higher oxygen consumption during the both light and dark phase than high-fat fed male Cbl^tm1Ddlb /+ heterozygous littermates at 18-24 weeks of age

improved glucose tolerance ( J:121012 )

• mice show significanty enhanced glucose clearance compared to Cbl^tm1Ddlb /+ heterozygous littermates 18-24 weeks old

• high-fat-fed male mice have a greater ability to clear glucose after intraperitoneal glucose injection than high-fat fed high-fat-fed Cbl^tm1Ddlb /+ heterozygous littermates; plasma glucose levels are close to basal levels within 90 minutes

increased insulin sensitivity ( J:121012 )

• in males, peripheral insulin sensitivity is increased compared to controls

abnormal enzyme/coenzyme activity ( J:121012 )

• cytochrome c oxidase and b-hydroxyacyl-CoA dehydrogenase activities are significantly elevated in skeletal muscle