Phenotypes associated with this allele

• Allele Symbol: Stat3^tm1Flv
• Allele Name: targeted mutation 1, Richard A Flavell
• Allele ID: MGI:2451328
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Stat3^tm1Flv/Stat3^tm1Flv Tg(Tek-cre)12Flv/0	involves: 129 * C3H * C57BL/6	MGI:3783296
cn2	Stat3^tm1Flv/Stat3^tm1Flv Tg(Tek-cre)1Xyfu/0	involves: C57BL/6	MGI:2683230
cn3	Stat3^tm1Flv/Stat3^tm1Flv Tg(Nes-cre)1Kln/0	involves: C57BL/6 * SJL	MGI:3783343

Genotype
MGI:3783296

cn1

• Allelic Composition: Stat3^tm1Flv/Stat3^tm1Flv; Tg(Tek-cre)12Flv/0
• Genetic Background: involves: 129 * C3H * C57BL/6

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

Crohn's disease-like pathogenesis in Stat3^tm1Flv/Stat3^tm1Flv Tg(Tek-cre)12Flv/0 mice

mortality/aging

premature death ( J:81973 )

• die within 4-6 weeks after birth, and none survive more than 8 weeks

growth/size/body

decreased body size ( J:81973 )

• mutants are smaller at 3-4 weeks of age

decreased body weight ( J:81973 )

• reduced body weight is seen at 3-4 weeks of age

behavior/neurological

weakness ( J:81973 )

• mutants appear fragile and weak by 4-6 weeks of age

immune system

increased leukocyte cell number ( J:81973 )

• bone marrow shows an expansion of GR-1+Mac1+ neutrophil lineage (20% in controls vs. 35% in mutants), indicating an abnormal expansion of a myeloid lineage in the bone marrow

• lethally irradiated recipients of mutant bone marrow show much higher numbers of attached Mac1+ cells than controls and mutant bone marrow cultured in the presence of CSF-1 shows an increase in the generation of attached macrophages than controls indicating cell autonomous overproduction of myeloid cells

abnormal T-helper 1 physiology ( J:81973 )

• deregulated T helper 1-type immune response

increased circulating interferon-gamma level ( J:81973 )

increased circulating tumor necrosis factor level ( J:81973 )

• increase in TNF-alpha levels

abnormal inflammatory response ( J:81973 )

intestinal inflammation ( J:81973 )

• massive infiltration of the intestine with neutrophils, macrophages, and eosinophils

• myeloid cells, rather than lymphocytes, are the major cell populations in the inflammatory infiltrates of the gastrointestinal tract

cecum inflammation ( J:81973 )

• a transmural inflammation of all layers of the cecum is observed

colitis ( J:81973 )

• a transmural inflammation of all layers of the colon is observed

ileum inflammation ( J:81973 )

• transmural inflammation

granulomatous inflammation ( J:81973 )

• granuloma-like structures in the ileocecal area

liver inflammation ( J:81973 )

• the liver shows infiltration of granulocytes around the portal vein

abnormal innate immunity ( J:81973 )

• mutants show overly pseudoactivated innate immune responses

digestive/alimentary system

abnormal intestine morphology ( J:81973 )

• intestine shows ulceration, bowel wall thickening, granuloma formation, and segmental inflammatory cell infiltration

intestinal ulcer ( J:81973 )

abnormal cecum morphology ( J:81973 )

• ulceration and a transmural inflammation of all layers of the cecum is observed

• cecum exhibits crypt abscesses with necrotic neutrophils and monocytes, high frequency of mitosis in the epithelium, edema of the lamina propria and epithelioid cells with eosinophilic cytoplasm

abnormal colon morphology ( J:81973 )

• colon of 4-week old mutants shows bowel wall thickening, mucosal erosion, transmural inflammation affecting all layers, edema in the submucosa, and serosa thickening

abnormal ileum morphology ( J:81973 )

• ileum is fused to the peritoneal wall in severely sick mutants

• ileum shows ulceration, loss of mucosal texture, transmural inflammation, granuloma-like structures and abnormal changes in the mucosa, submucosa, smooth muscle and serosa

intestinal inflammation ( J:81973 )

• massive infiltration of the intestine with neutrophils, macrophages, and eosinophils

• myeloid cells, rather than lymphocytes, are the major cell populations in the inflammatory infiltrates of the gastrointestinal tract

cecum inflammation ( J:81973 )

• a transmural inflammation of all layers of the cecum is observed

colitis ( J:81973 )

• a transmural inflammation of all layers of the colon is observed

ileum inflammation ( J:81973 )

• transmural inflammation

hematopoietic system

increased leukocyte cell number ( J:81973 )

• bone marrow shows an expansion of GR-1+Mac1+ neutrophil lineage (20% in controls vs. 35% in mutants), indicating an abnormal expansion of a myeloid lineage in the bone marrow

• lethally irradiated recipients of mutant bone marrow show much higher numbers of attached Mac1+ cells than controls and mutant bone marrow cultured in the presence of CSF-1 shows an increase in the generation of attached macrophages than controls indicating cell autonomous overproduction of myeloid cells

abnormal T-helper 1 physiology ( J:81973 )

• deregulated T helper 1-type immune response

homeostasis/metabolism

increased circulating interferon-gamma level ( J:81973 )

increased circulating tumor necrosis factor level ( J:81973 )

• increase in TNF-alpha levels

decreased NAD(P)H oxidase activity ( J:81973 )

• NADPH oxidase activity of neutrophils is reduced to 45% compared to more than 90% in controls

liver/biliary system

liver inflammation ( J:81973 )

• the liver shows infiltration of granulocytes around the portal vein

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
inflammatory bowel disease		DOID:0050589	OMIM:PS266600	J:81973

Genotype
MGI:2683230

cn2

• Allelic Composition: Stat3^tm1Flv/Stat3^tm1Flv; Tg(Tek-cre)1Xyfu/0
• Genetic Background: involves: C57BL/6

immune system

abnormal cytokine secretion ( J:86655 )

• LPS elicits increased and prolonged proinflammatory cytokine production, with increases in TNF-alpha, IL-6, IFN-gamma, and IL-10

increased susceptibility to endotoxin shock ( J:86655 )

• increased lethality after LPS challenge, with exaggerated inflammation and leukocyte infiltration in multiple organs

• organ damage indicated by increased serum alanine and aspartate aminotransferase activities

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
inflammatory bowel disease		DOID:0050589	OMIM:PS266600	J:86655

Genotype
MGI:3783343

cn3

• Allelic Composition: Stat3^tm1Flv/Stat3^tm1Flv; Tg(Nes-cre)1Kln/0
• Genetic Background: involves: C57BL/6 * SJL

Neural-specific STAT3 deletion results in severe obesity in Stat3^tm1Flv/Stat3^tm1Flv Tg(Nes-cre)1Kln/0 mice similar to that seen in Lepr^db/Lepr^db mice

mortality/aging

neonatal lethality, incomplete penetrance ( J:89242 )

• reducing the number of pups to lower the competition for milk rescues a substantial proportion of mutants from neonatal lethality

growth/size/body

obese ( J:89242 )

• mutants that survive the neonatal period develop obesity by 6-9 weeks of age and weigh twice as much as controls as adults

decreased body length ( J:89242 )

• mutants are about 8% shorter than controls

enlarged liver ( J:89242 )

liver/biliary system

enlarged liver ( J:89242 )

hepatic steatosis ( J:89242 )

adipose tissue

increased total body fat amount ( J:89242 )

• total fat content is increased 5-fold compared to controls, however lean mass is unchanged

abnormal brown adipose tissue morphology ( J:89242 )

• brown adipose tissue becomes diffuse and the structure resembles white adipose tissue

abnormal white adipose tissue morphology ( J:89242 )

• white adipose cells are larger in mutants

homeostasis/metabolism

impaired adaptive thermogenesis ( J:89242 )

• after a 12 hour fast mutants become hypothermic, however this is reversed after 1.5 hours of refeeding

• mutants housed at 4 degrees C for 3.5 hours cannot maintain their body temperature like wild-type and drop about 1 degree in body temperature every 30 min until they reach 34 degrees C, at which point they stabilize this temperature, indicating decreased sympathetic activity

increased circulating corticosterone level ( J:89242 )

increased circulating leptin level ( J:89242 )

increased circulating triglyceride level ( J:89242 )

decreased body temperature ( J:89242 )

• in the fed state, mutants show a slight but significantly lowered body temperature

abnormal body temperature homeostasis ( J:89242 )

• in the fed state, mutants show a slight but significantly lowered body temperature, however mutants are able to stabilize their body temperature by consuming twice as much food

decreased energy expenditure ( J:89242 )

abnormal glucose homeostasis ( J:89242 )

hyperglycemia ( J:89242 )

• plasma fasting glucose concentrations are increased

increased circulating insulin level ( J:89242 )

• plasma insulin concentrations are as much as 14- and 10-fold higher in the fed and fasted state, respectively

impaired glucose tolerance ( J:89242 )

• plasma glucose and insulin concentrations increase 5-fold after glucose challenge compared to controls

insulin resistance ( J:89242 )

• plasma insulin concentrations are as much as 14- and 10-fold higher in the fed and fasted state, respectively, indicating insulin resistance

behavior/neurological

decreased food intake ( J:89242 )

• pups contain reduced amount of milk in stomachs

polyphagia ( J:89242 )

• mutants consume twice as much food as wild-type

• administration of a malanocortin-3/4 receptor, MTII, reverses their hyperphagia over a 4 hour period

endocrine/exocrine glands

small seminal vesicle ( J:89242 )

♂

absent corpus luteum ( J:89242 )

♀

small testis ( J:89242 )

♂

reproductive system

small seminal vesicle ( J:89242 )

♂

absent corpus luteum ( J:89242 )

♀

small testis ( J:89242 )

♂

short uterine horn ( J:89242 )

♀ • reduced size of uterine horns

anovulation ( J:89242 )

♀ • corpa lutea are never observed indicating that ovulation does not occur

female infertility ( J:89242 )

♀

male infertility ( J:89242 )

♂