Phenotypes Associated with This Genotype

Genotype
MGI:2174941

• Allelic Composition: Cebpb^tm1Vpo/Cebpb^tm1Vpo
• Genetic Background: involves: 129S/SvEv * MF1

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

mortality/aging

premature death ( J:25215 )

• homozygotes raised in a non-specific pathogen-free facility display an additional 50% increase in mortality during the first few weeks post-weaning

postnatal lethality, incomplete penetrance ( J:25215 )

• only 12% of homozygotes, instead of the expected Mendelian ratio of 25%, are obtained at weaning, indicating postnatal lethality

hematopoietic system

enlarged spleen ( J:25215 )

• starting at 16 weeks of age, homozygotes exhibit splenomegaly

abnormal definitive hematopoiesis ( J:25215 )

extramedullary hematopoiesis ( J:25215 )

• homozygotes exhibit extramedullary hematopoiesis in the spleen, lymph nodes (partial penetrance) and liver (not shown)

• 6 of 20 homozygotes contain lymph nodes with myelocytes present at varying stages of maturation, suggesting deregulated hematopoietic proliferation

increased bone marrow cell number ( J:25215 )

• homozygotes show bone marrow hyperplasia with a prevalence of myeloblasts, mature granulocytes and megakaryocytes

abnormal plasma cell morphology ( J:25215 )

• in addition to extensive plasmacytosis in the spleen and lymph nodes, homozygotes show significant infiltration of plasma cells in the peribronchial region of the lung, kidney stroma, and in portal areas of the liver

abnormal spleen red pulp morphology ( J:25215 )

• homozygotes display a hyperplastic red pulp, with many aggregates of plasma cells intermixed with hematopoietic tissue containing numerous megakaryocytes and mature granulocytes

• in severely enlarged spleens, the red pulp is engulfed by erythroid cells

abnormal spleen white pulp morphology ( J:25215 )

• homozygotes display a hyperplastic white pulp relative to wild-type mice

abnormal spleen secondary B follicle morphology ( J:25215 )

• homozygotes exhibit large lymphoid follicles with wide germinal centers in the white pulp

• homozygotes develop an age-related expansion of the B-cell compartment in the spleen, as shown by abnormally high numbers of B220⁺ cells

increased IgG level ( J:25215 )

• ageing homozygotes spontaneously display high levels of IgG-bearing cells relative to wild-type mice

abnormal T-helper 1 physiology ( J:25215 )

• in response to systemic candidiasis, homozygotes exhibit an impaired Th1-type response and a strong Th2-type response, in accord with a reactive lymphoproliferative disorder

abnormal T-helper 2 physiology ( J:25215 )

• in response to systemic candidiasis, homozygotes develop a non-protective Th2-biased response, as shown by elevated levels of Candida-specific antibodies of the IgG1 rather than the IgG2a isotype

• Th2 cytokines IL-4 and IL-6 are increasingly produced by CD4⁺ cells in Candida-susceptible homozygotes, while progressively disappearing in resistant wild-type mice

abnormal macrophage physiology ( J:25215 )

• upon in vitro activation with IFN-gamma plus LPS, splenic macrophages obtained from mutant mice fail to release nitric oxide, either before or after C. albicans infection

• notably, mutant splenic macrophages display significantly reduced candidacidal activity relative to wild-type macrophages

homeostasis/metabolism

decreased circulating leptin level ( J:62132 )

• at 16-20 weeks, reduced adipose tissue mass is associated with significantly reduced plasma leptin levels

decreased circulating interleukin-12 level ( J:25215 )

• in response to systemic candidiasis, homozygotes fail to exhibit a significant increase in serum IL-12 levels, indicating an impaired Th1 response

increased circulating interleukin-6 level ( J:25215 )

• nearly all homozygotes (only males studied) exhibit significantly increased serum IL-6 levels, with mean values increasing with age

abnormal enzyme/coenzyme level ( J:52286 )

• adult fed female homozygotes show a 42% reduction in adipose tissue cAMP levels relative to wild-type mice; in addition, both basal and glucagon-stimulated hepatic cAMP levels are significantly reduced

abnormal glucose homeostasis ( J:52286 , J:62132 )

• after an 18-hr overnight fast, adult female homozygotes exhibit an ~40% reduction in basal hepatic glucose production (HGP) relative to wild-type mice (J:52286)

• during a pancreatic clamp, overnight-fasted female homozygotes show glucagon resistance, failing to exhibit a significant increase in HGP in response to glucagon infusion; in contrast, wild-type mice respond to glucagon stimulation by a ~38% increase in HGP (J:52286)

• at 16-20 weeks, homozygotes exhibit a significant increase in whole-body insulin-stimulated glucose disposal along with accelerated glucose metabolism in skeletal muscle (J:62132)

hypoglycemia ( J:52286 , J:62132 )

• in the fed state, adult female homozygotes exhibit normal plasma glucose levels relative to wild-type mice (J:52286)

• after an 18-hr overnight fast, female homozygotes exhibit hypoglycemia, with plasma glucose levels ~30% lower than wild-type levels while insulin levels remain relatively normal (J:52286)

• fasting hypoglycemia is associated with normal levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase gene expression, despite a reduction in net liver glycogenolysis (J:52286)

• after a 6-hr fast, adult homozygotes exhibit a 25% reduction in plasma glucose levels relative to wild-type mice (J:62132)

decreased circulating insulin level ( J:62132 )

• after a 6-hr fast, adult homozygotes exhibit a 35% reduction in plasma insulin levels relative to wild-type mice

abnormal gluconeogenesis ( J:52286 )

• adult female homozygotes exhibit reduced gluconeogenesis during fasting

decreased glycogen catabolism rate ( J:52286 )

• at the end of pancreatic clamp, adult female homozygotes show a 22% reduction in net hepatic glycogen depletion, suggesting a defect in hepatic glycogen mobilization in response to fasting and glucagon infusion

increased insulin sensitivity ( J:62132 )

• adult homozygotes exhibit increased whole-body insulin sensitivity, probably as a result of reduced plasma FFA levels and enhanced insulin signaling in skeletal muscle

• increased insulin-stimulated glucose disposal is primarily due to an increase in glucose uptake in peripheral tissues rather than enhanced suppression of HGP by insulin

• in contrast to enhanced insulin action in skeletal muscle, adult homozygotes exhibit a normal metabolic and gene regulatory response to insulin in liver and adipose tissue

hemosiderosis ( J:25215 )

• homozygotes exhibit hemosiderosis in the red pulp of the spleen

abnormal lipid homeostasis ( J:52286 , J:62132 )

• after an 18-hr overnight fast, adult female homozygotes show a 40% increase in the amount of DNA per gram of adipose tissue, suggesting reduced lipid content per cell (J:52286)

increased circulating corticosterone level ( J:52286 )

• after an 18-hr overnight fast, adult female homozygotes exhibit a slight increase in circulating corticosterone levels relative to wild-type mice

abnormal circulating free fatty acids level ( J:52286 )

• in response to epinephrine, adult fed homozygotes show a 68% reduction in FFA release from periovarian fat-pads relative to wild-type mice, indicating impaired lipolysis

• notably, Bt2 cAMP, augments FFA release 2-fold above epinephrine-stimulated FFA levels in mutant females, compared with no additional change in wild-type mice

decreased circulating free fatty acids level ( J:52286 , J:62132 )

• at the end of a pancreatic clamp, overnight-fasted adult homozygotes show a 50% reduction in FFA and 3-hydroxybutyrate levels relative to wild-type mice; a 43% decrease in plasma lactate levels is also observed (J:52286)

• adult homozygotes show reduced fasting plasma FFA levels before a hyperinsulinemic clamp and during the first 100 min of insulin infusion; after 100 min of hyperinsulinemia, mutant and wild-type mice show a comparable level of suppression of plasma FFA (J:62132)

decreased circulating triglyceride level ( J:52286 )

• after an 18-hr overnight fast, adult female homozygotes show a 31% reduction in circulating triglyceride levels relative to wild-type mice

impaired lipolysis ( J:62132 )

• impaired lipolysis i.e. FFA release from mutant periovarian fat-pads is most likely due to inability to generate cAMP in response to epinephrine

muscle

increased skeletal muscle cell glucose uptake ( J:62132 )

• in vitro, skeletal muscles from homozygotes show increased insulin-stimulated glucose transport activity and elevated IRS-1 protein levels

immune system

enlarged spleen ( J:25215 )

• starting at 16 weeks of age, homozygotes exhibit splenomegaly

abnormal plasma cell morphology ( J:25215 )

• in addition to extensive plasmacytosis in the spleen and lymph nodes, homozygotes show significant infiltration of plasma cells in the peribronchial region of the lung, kidney stroma, and in portal areas of the liver

abnormal spleen red pulp morphology ( J:25215 )

• homozygotes display a hyperplastic red pulp, with many aggregates of plasma cells intermixed with hematopoietic tissue containing numerous megakaryocytes and mature granulocytes

• in severely enlarged spleens, the red pulp is engulfed by erythroid cells

abnormal spleen white pulp morphology ( J:25215 )

• homozygotes display a hyperplastic white pulp relative to wild-type mice

abnormal spleen secondary B follicle morphology ( J:25215 )

• homozygotes exhibit large lymphoid follicles with wide germinal centers in the white pulp

• homozygotes develop an age-related expansion of the B-cell compartment in the spleen, as shown by abnormally high numbers of B220⁺ cells

decreased circulating interleukin-12 level ( J:25215 )

• in response to systemic candidiasis, homozygotes fail to exhibit a significant increase in serum IL-12 levels, indicating an impaired Th1 response

increased circulating interleukin-6 level ( J:25215 )

• nearly all homozygotes (only males studied) exhibit significantly increased serum IL-6 levels, with mean values increasing with age

enlarged mesenteric lymph nodes ( J:25215 )

• homozygotes exhibit enlarged mesenteric lymph nodes relative to wild-type mice

abnormal lymph node cortex morphology ( J:25215 )

abnormal lymph node B cell domain morphology ( J:25215 )

abnormal lymph node secondary follicle morphology ( J:25215 )

• homozygotes have hyperplastic lymphoid follicles and enlarged germinal centers containing lymphocytes in varying stages of "blast" transformation in the cortex

• homozygotes develop an age-related expansion of the B-cell compartment in the lymph nodes, as shown by abnormally high numbers of B220⁺ cells

abnormal lymph node T cell domain morphology ( J:25215 )

• homozygotes contain numerous sheets and aggregates of mostly mature plasma cells in the compressed paracortical region of hyperplastic lymph nodes

abnormal lymph node medulla morphology ( J:25215 )

• homozygotes exhibit an enlarged medulla

abnormal lymph node medullary cord morphology ( J:25215 )

• homozygotes exhibit medullary cords packed with sheets and aggregates of mostly mature plasma cells in pseudotumoral arrangement

enlarged lymph nodes ( J:25215 )

• starting at 16 weeks of age, homozygotes display enlarged peripheral lymph nodes (lymphoadenopathy)

enlarged axillary lymph nodes ( J:25215 )

• homozygotes exhibit enlarged lacrimal and peribronchial lymph nodes relative to wild-type mice

enlarged inguinal lymph nodes ( J:25215 )

• homozygotes exhibit enlarged inguinal lymph nodes relative to wild-type mice

enlarged submandibular lymph nodes ( J:25215 )

abnormal mucosa-associated lymphoid tissue morphology ( J:25215 )

• starting at 16 weeks of age, homozygotes exhibit mucosal swelling

abnormal cell-mediated immunity ( J:25215 )

abnormal T-helper 1 physiology ( J:25215 )

• in response to systemic candidiasis, homozygotes exhibit an impaired Th1-type response and a strong Th2-type response, in accord with a reactive lymphoproliferative disorder

abnormal T-helper 2 physiology ( J:25215 )

• in response to systemic candidiasis, homozygotes develop a non-protective Th2-biased response, as shown by elevated levels of Candida-specific antibodies of the IgG1 rather than the IgG2a isotype

• Th2 cytokines IL-4 and IL-6 are increasingly produced by CD4⁺ cells in Candida-susceptible homozygotes, while progressively disappearing in resistant wild-type mice

decreased susceptibility to type IV hypersensitivity reaction ( J:25215 )

• in response to systemic candidiasis, homozygotes show impaired DTH reactivity (measured as footpad weight increase) at 10 days after PCA-2 infection, indicating an impaired Th1-type response

abnormal humoral immune response ( J:25215 )

increased IgG level ( J:25215 )

• ageing homozygotes spontaneously display high levels of IgG-bearing cells relative to wild-type mice

glomerulonephritis ( J:25215 )

abnormal innate immunity ( J:25215 )

abnormal macrophage physiology ( J:25215 )

• upon in vitro activation with IFN-gamma plus LPS, splenic macrophages obtained from mutant mice fail to release nitric oxide, either before or after C. albicans infection

• notably, mutant splenic macrophages display significantly reduced candidacidal activity relative to wild-type macrophages

increased susceptibility to fungal infection ( J:25215 )

• homozygotes are more susceptible to a low inoculum (i.v., 10⁵ cells) of the CA-6 strain of C. albicans, with ~88% homozygotes dying within 14 days while all wild-type mice survive

• both wild-type and mutant mice survive challenge with 10⁶ cells of the low virulence PCA-2 strain; however, unlike wild-type mice, homozygotes fail to survive a subsequent lethal CA-6 challenge, with a high number of C. albicans cells found in the kidney

• increased susceptibility to C. albicans infection is associated with predominance of a Th2-type response

renal/urinary system

increased mesangial cell number ( J:25215 )

• 7 of 20 homozygotes exhibit an increase in mesangial cells

glomerulonephritis ( J:25215 )

expanded mesangial matrix ( J:25215 )

• 7 of 20 homozygotes exhibit an increase in mesangial matrix

renal glomerulus hypertrophy ( J:25215 )

• 7 of 20 homozygotes show enlarged glomeruli

adipose tissue

decreased gonadal fat pad weight ( J:62132 )

• at 16-20 weeks, adult homozygotes show a ~38% reduction in gonadal fat pad weight relative to wild-type mice

decreased uterine fat pad weight ( J:52286 )

• after an 18-hr overnight fast, adult female homozygotes exhibit an ~50% reduction in the weight of periuterine fat-pad relative to wild-type mice

decreased percent body fat/body weight ( J:62132 )

• at 16-20 weeks, homozygotes show a 38% reduction in total body lipid content relative to wild-type mice; however, the average body weight is not significantly altered

abnormal adipose tissue physiology ( J:52286 )

• adult fed female homozygotes show a 42% reduction in adipose tissue cAMP levels relative to wild-type mice

• impaired lipolysis i.e. FFA release from mutant periovarian fat-pads is most likely due to inability to generate cAMP in response to epinephrine

integument

skin lesions ( J:25215 )

• homozygotes raised under SPF conditions develop skin lesions with increasing age

• skin lesions are more frequent and severe and appear earlier in homozygotes exposed to pathogens

cellular

increased mesangial cell number ( J:25215 )

• 7 of 20 homozygotes exhibit an increase in mesangial cells

increased skeletal muscle cell glucose uptake ( J:62132 )

• in vitro, skeletal muscles from homozygotes show increased insulin-stimulated glucose transport activity and elevated IRS-1 protein levels

growth/size/body

enlarged spleen ( J:25215 )

• starting at 16 weeks of age, homozygotes exhibit splenomegaly

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
viral infectious disease		DOID:934		J:25215