Phenotypes associated with this allele

• Allele Symbol: Ptpn11^tm1Gsf
• Allele Name: targeted mutation 1, Gen-Sheng Feng
• Allele ID: MGI:3522021
• Summary: 12 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Ptpn11^tm1Gsf/Ptpn11^tm1Gsf Stat3^tm1Vpo/Stat3^tm1Vpo Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA	MGI:5009547
cn2	Ptpn11^tm1Gsf/Ptpn11^tm1Gsf Tg(Col2a1-cre/ERT2)1Dic/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:5788097
cn3	Ptpn11^tm1Gsf/Ptpn11^tm1Gsf Tg(Camk2a-cre)2Szi/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA	MGI:3522138
cn4	Ptpn11^tm1Gsf/Ptpn11^tm1Gsf Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA	MGI:5009546
cn5	Pten^tm1Hwu/Pten^tm1Hwu Ptpn11^tm1Gsf/Ptpn11^tm1Gsf Tg(Six3-cre)69Frty/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2	MGI:6384016
cn6	Kras^tm4Tyj/Kras^tm4Tyj Ptpn11^tm1Gsf/Ptpn11^tm1Gsf Tg(Six3-cre)69Frty/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2	MGI:6384017
cn7	Ptpn11^tm1Gsf/Ptpn11^tm1Gsf Tg(Six3-cre)69Frty/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2	MGI:6384014
cn8	Ptpn11^tm1Gsf/Ptpn11^tm1Gsf Stat3^tm1Xyfu/Stat3^tm1Xyfu Tg(Six3-cre)69Frty/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2	MGI:6384015
cn9	Ptpn11^tm1Gsf/Ptpn11^tm1Gsf Plekha5^Tg(AMH-cre)1Flor/Plekha5^+	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL	MGI:7281502
cn10	Ptpn11^tm1Gsf/Ptpn11^tm1Gsf Tg(Inha-cre)3Zuk/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL	MGI:7281516
cn11	Ptpn11^tm1Gsf/Ptpn11^tm1Gsf Tg(Pax6-cre,GFP)1Pgr/0	involves: 129S1/Sv * 129X1/SvJ * FVB	MGI:4943280
cn12	Ptpn11^tm1Gsf/Ptpn11^tm1Gsf Tg(Ckmm-cre)5Khn/0	involves: 129S1/Sv * 129X1/SvJ * FVB	MGI:5906203

Genotype
MGI:5009547

cn1

• Allelic Composition: Ptpn11^tm1Gsf/Ptpn11^tm1Gsf; Stat3^tm1Vpo/Stat3^tm1Vpo; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA

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

homeostasis/metabolism

increased circulating alanine transaminase level ( J:172422 )

• increase in serum ALT levels, however ALT levels are lower than in single conditional Ptpn11 mice

increased incidence of tumors by chemical induction ( J:172422 )

• mutants exhibit an increase in hepatocellular carcinoma development after diethylnitrosamine (DEN) injection compared to controls and single conditional Ptpn11 mutants, however tumor frequency and size are similar to that seen in single conditional Stat3 mutants

immune system

liver inflammation ( J:172422 )

• infiltrate of inflammatory cells is seen in the portal triads of livers

• double mutants show less inflammation than seen in single conditional Ptpn11 mice, with reduced size of eosinophilic vacuoles of degeneration in the liver

liver/biliary system

liver inflammation ( J:172422 )

• infiltrate of inflammatory cells is seen in the portal triads of livers

• double mutants show less inflammation than seen in single conditional Ptpn11 mice, with reduced size of eosinophilic vacuoles of degeneration in the liver

neoplasm

increased incidence of tumors by chemical induction ( J:172422 )

• mutants exhibit an increase in hepatocellular carcinoma development after diethylnitrosamine (DEN) injection compared to controls and single conditional Ptpn11 mutants, however tumor frequency and size are similar to that seen in single conditional Stat3 mutants

Genotype
MGI:5788097

cn2

• Allelic Composition: Ptpn11^tm1Gsf/Ptpn11^tm1Gsf; Tg(Col2a1-cre/ERT2)1Dic/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

behavior/neurological

abnormal gait ( J:324822 )

• following tamoxifen treatment at 4 weeks of age

skeleton

skeleton phenotype ( J:324822 )

N • segmentation of individual vertebra bodies appears normal at 12 weeks of age after tamoxifen treatment at 4 weeks of age

abnormal vertebral column morphology ( J:324822 )

• progressive spinal deformity seen at 2-3 weeks after tamoxifen treatment starting at 4 weeks of age

• seen in about 40% of mice after tamoxifen treatment at 4 weeks of age

• however, following tamoxifen treatment at 8 weeks of age no spinal deformity is seen in mice at up to 16 weeks of age

abnormal spine curvature ( J:324822 )

• rotational deformity is also seen

kyphosis ( J:324822 )

• severe in the lower thoracic to lumbar spine

lordosis ( J:324822 )

• severe lordosis in the upper thoracic spine

scoliosis ( J:324822 )

• scoliosis is in the region of the lower thoracic and lumbar spine

kyphoscoliosis ( J:324822 )

• severe at 12 weeks of age following tamoxifen treatment at 4 weeks of age

• Cobb angle of the lumbar spine is about 90 degrees

abnormal vertebral epiphyseal plate morphology ( J:324822 )

• following tamoxifen treatment at 4 weeks of age, vertebra endplates show disorganized growth plate cartilage, variable cartilage thickness and absent columnar formation of chondrocytes

• height of growth plate cartilage appears increased

exostosis ( J:233244 )

• mice treated with tamoxifen at 4 weeks of age develop exostosis in the metacarpal-phalangeal and metatarsal-phalangeal joints and the distal radius/ulna with continuity from the metaphyseal bone adjacent to the growth plate

• mice first develop nodule formations in the dorsal hands and feet and in the wrist and ankle joints 2 weeks after tamoxifen treatment

• bony nodules in the hands of tamoxifen treated mice arise from the metaphyseal region of the metacarpal bone and cartilaginous matrix in the nodules originates form the groove of Ranvier

• cartilaginous nodules in the feet of tamoxifen treated mice form in the metaphysis of the distal metatarsal bones

ectopic cartilage ( J:233244 )

• tamoxifen treated mice develop enchondroma-like (ectopic cartilaginous nodules inside the bone) cartilage lesions in the ribs

• tamoxifen treated mice show irregular rib cartilage surface and disorganized column formation in the rib growth plate cartilage , prominent hypertrophic chondrocyte clusters at the perichondrium-to-rib cartilage junction, and multiple cartilage islands within the rib trabecular bone

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
idiopathic scoliosis		DOID:0060250		J:324822

Genotype
MGI:3522138

cn3

• Allelic Composition: Ptpn11^tm1Gsf/Ptpn11^tm1Gsf; Tg(Camk2a-cre)2Szi/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA

adipose tissue

increased brown adipose tissue amount ( J:94738 )

• at 8 weeks of age, males had 9% more brown adipose tissue and females had 80% more than controls

increased white adipose tissue amount ( J:94738 )

• at 8 weeks of age, male mutants had 32% more white adipose tissue and females had 123% more than controls

endocrine/exocrine glands

hypersecretion of corticosterone ( J:94738 )

growth/size/body

obese ( J:94738 )

• at 8 weeks of age, males and females gained 28% and 21%, respectively, more weight than wild-types or heterozygotes, developing early-onset obesity

• male and female adults weighed ~30 to 50% more than wild-type

increased body length ( J:94738 )

• increased snout-anus length

increased susceptibility to weight gain ( J:94738 )

• male mutants gained 150% of body weight between P23-32 compared with controls while females gained 172% of body weight compared with controls despite similar or slightly reduced amounts of food consumption

enlarged liver ( J:94738 )

• liver size was increased by 12% in males, with a lesser extent of increase in females

homeostasis/metabolism

abnormal circulating hormone level ( J:94738 )

decreased circulating thyroxine level ( J:94738 )

• lower thyroxine levels in 13-15 week old females

decreased circulating triiodothyronine level ( J:94738 )

• modestly decreased serum triiodothyronine levels in 13-15 week old females

increased circulating corticosterone level ( J:94738 )

increased circulating insulin level ( J:94738 )

• mutants in both the fed and fasting states showed an increase in insulin levels

increased circulating leptin level ( J:94738 )

• 2.7-fold and 4.6-fold increase in serum leptin levels in male and female mutants, respectively

increased circulating growth hormone level ( J:94738 )

• hypersecretion of growth hormone was observed in male mutants and to a lesser extent in females

increased circulating thyroid-stimulating hormone level ( J:94738 )

• increased serum thyroid-stimulating hormone levels in 13-15 week old females

increased circulating triglyceride level ( J:94738 )

• 20% more serum triglyceride levels in both males and females

decreased body temperature ( J:94738 )

• significantly lower body temperature (35.8 versus 36.5C)

abnormal glucose homeostasis ( J:94738 )

hypoglycemia ( J:94738 )

• mutants fasted for 20 hours became hypoglycemic compared to controls

hyperglycemia ( J:94738 )

• hyperglycemic at 8 weeks of age when fed a normal diet

increased liver glycogen level ( J:94738 )

• elevated glycogen deposits in livers

increased liver triglyceride level ( J:94738 )

• abnormal accumulation of triglycerides in the liver

liver/biliary system

abnormal liver morphology ( J:94738 )

• abnormal accumulation of triglycerides and elevated glycogen deposits in the liver

enlarged liver ( J:94738 )

• liver size was increased by 12% in males, with a lesser extent of increase in females

increased liver glycogen level ( J:94738 )

• elevated glycogen deposits in livers

increased liver triglyceride level ( J:94738 )

• abnormal accumulation of triglycerides in the liver

hepatic steatosis ( J:94738 )

• fatty liver in 15-week old mutants

reproductive system

reduced female fertility ( J:94738 )

♀ • for 3 months, 8/12 mutant females delivered pups, and the average litter number was 45% of controls

Genotype
MGI:5009546

cn4

• Allelic Composition: Ptpn11^tm1Gsf/Ptpn11^tm1Gsf; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA

growth/size/body

weight loss ( J:172422 )

• aged mutants become leaner by 10.7% for males and 14.9% for females, with a significant decrease of their body weights at 1 year of age

liver hyperplasia ( J:172422 )

• lobular architecture of the liver is distorted by the development of hyperplastic hepatocyte plates

homeostasis/metabolism

increased circulating interleukin-6 level ( J:172422 )

increased circulating alanine transaminase level ( J:172422 )

• serum levels of alanine aminotransferase are higher than in controls

increased circulating aspartate transaminase level ( J:172422 )

• serum levels of aspartate aminotransferase are higher than in controls

increased incidence of tumors by chemical induction ( J:172422 )

• injection of a single dose of diethylnitrosamine (DEN) on P15 results in an increase in the number and size of (hepatocellular carcinoma) liver tumors in mutants compared to controls

immune system

increased circulating interleukin-6 level ( J:172422 )

increased acute inflammation ( J:172422 )

• intraperitoneal LPS injection elicits a stronger liver damage response in mutants than in controls as indicated by higher serum alanine aminotransferase levels

• mutants show a 130% increase in spleen size 14 days after LPS challenge as compared to 98% increase in controls indicating increased systemic inflammatory response

• mutants show increased inflammatory cell infiltration into hepatic parenchyma after LPS challenge

• circulating IL-6 and TNFalpha levels are increased following LPS injection

• LPS stimulation of isolated hepatocytes results in increased IL-6 secretion by mutant hepatocytes compared to controls

liver inflammation ( J:172422 )

• 93% of mutant livers contain areas with infiltrate of inflammatory cells, concentrating around the portal triads with extension into the parenchyma

• necrotic zones of livers are always associated with inflammatory cells, whereas inflammation is occasionally observed without necrosis

• 8 of 19 aged mutants develop focal microgranuloma consisting of mononuclear inflammatory cells

liver/biliary system

increased hepatocyte proliferation ( J:172422 )

liver inflammation ( J:172422 )

• 93% of mutant livers contain areas with infiltrate of inflammatory cells, concentrating around the portal triads with extension into the parenchyma

• necrotic zones of livers are always associated with inflammatory cells, whereas inflammation is occasionally observed without necrosis

• 8 of 19 aged mutants develop focal microgranuloma consisting of mononuclear inflammatory cells

abnormal liver morphology ( J:172422 )

• one or several foci of pallor are noticeable on the liver surface of 34% of analyzed mutants

• beginning at 5 months of age, regenerative foci are noticeable in the liver and nodular regenerative hyperplasia is seen from 8 months of age

• hepatic inflammation and necrosis, leading to nodular regenerative hyperplasia

liver hyperplasia ( J:172422 )

• lobular architecture of the liver is distorted by the development of hyperplastic hepatocyte plates

abnormal liver parenchyma morphology ( J:172422 )

• hepatic parenchyma shows regenerative hyperplasia, with 13 of 19 livers having nodule formation

• the space between hepatocytes is reduced inside the nodules

abnormal hepatocyte morphology ( J:172422 )

• massive hepatocyte degeneration is seen inside of or surrounding the hyperplastic nodules, in association with vacuoles containing eosinophilic material, but not in the liver parenchyma

hepatic necrosis ( J:172422 )

• liver shows small focal areas as well as large areas of parenchymal necrosis, with necrosis observed in 47% of mutants

focal hepatic necrosis ( J:172422 )

• liver shows small focal areas of parenchymal necrosis

increased liver adenoma incidence ( J:172422 )

• from 12-18 months of age, one or a few hepatocellular adenomas are frequently seen in mutants; tumors bulge from the liver surface, are often paler than the hepatic parenchyma, but sometimes darker or red when accompanied by bleeding

• tumors are unencapsulated, well delimited and show expanding masses of hepatocytes

liver fibrosis ( J:172422 )

• fibrosis is seen at the portal triads but not near the necrosis or into the parenchyma

neoplasm

increased incidence of tumors by chemical induction ( J:172422 )

• injection of a single dose of diethylnitrosamine (DEN) on P15 results in an increase in the number and size of (hepatocellular carcinoma) liver tumors in mutants compared to controls

increased liver adenoma incidence ( J:172422 )

• from 12-18 months of age, one or a few hepatocellular adenomas are frequently seen in mutants; tumors bulge from the liver surface, are often paler than the hepatic parenchyma, but sometimes darker or red when accompanied by bleeding

• tumors are unencapsulated, well delimited and show expanding masses of hepatocytes

cellular

increased hepatocyte proliferation ( J:172422 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hepatocellular adenoma		DOID:0050868		J:172422

Genotype
MGI:6384016

cn5

• Allelic Composition: Pten^tm1Hwu/Pten^tm1Hwu; Ptpn11^tm1Gsf/Ptpn11^tm1Gsf; Tg(Six3-cre)69Frty/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2

vision/eye

retina ganglion cell degeneration ( J:174095 )

• much thinner at age P21

optic nerve atrophy ( J:174095 )

• much thinner at age P21

thin retina ganglion layer ( J:174095 )

• severe reduction at age P21

thin retina inner nuclear layer ( J:174095 )

• severe reduction at age P21

thin retina outer nuclear layer ( J:174095 )

• severe reduction at age P21

retina outer nuclear layer degeneration ( J:174095 )

• much thinner at age P21

retina degeneration ( J:174095 )

• much thinner at age P21

nervous system

retina ganglion cell degeneration ( J:174095 )

• much thinner at age P21

optic nerve atrophy ( J:174095 )

• much thinner at age P21

Genotype
MGI:6384017

cn6

• Allelic Composition: Kras^tm4Tyj/Kras^tm4Tyj; Ptpn11^tm1Gsf/Ptpn11^tm1Gsf; Tg(Six3-cre)69Frty/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2

vision/eye

vision/eye phenotype ( J:174095 )

N • normal retina morphology at age P21 and P120

N • normal optic nerve morphology at age P21 and P120

decreased a-wave amplitude ( J:174095 )

• with scotopic ERG using very bright flashes at age 3 months, but not as severe as mice with wildtype Kras allele

decreased b-wave amplitude ( J:174095 )

• with scotopic ERG using dim flashes at age 3 months, but not as severe as mice with wildtype Kras allele

• with photopic ERG using double flashes at age 3 months, but not as severe as mice with wildtype Kras allele

abnormal cone electrophysiology ( J:174095 )

• reduced b wave amplitude with photopic ERG using double flashes at age 3 months, but not as severe as mice with wildtype Kras allele

abnormal rod electrophysiology ( J:174095 )

• reduced saturated a wave amplitude with scotopic ERG using very bright flashes at age 3 months, but not as severe as mice with wildtype Kras allele

• reduced b wave amplitude with scotopic ERG using dim flashes at age 3 months, but not as severe as mice with wildtype Kras allele

Genotype
MGI:6384014

cn7

• Allelic Composition: Ptpn11^tm1Gsf/Ptpn11^tm1Gsf; Tg(Six3-cre)69Frty/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2

vision/eye

retina ganglion cell degeneration ( J:174095 )

• increased apoptosis at age P10

• normal levels of apoptosis between ages E16 and P7

optic nerve atrophy ( J:174095 )

• much thinner and with numerous vacuoles at age P21

thin retina ganglion layer ( J:174095 )

• severe reduction at age P21 and P120

• normal at age P7

abnormal retina inner nuclear layer morphology ( J:174095 )

• increased apoptosis between age P10 and P14

thin retina inner nuclear layer ( J:174095 )

• normal at age P7

• severe reduction at age P21 and P120

thin retina inner plexiform layer ( J:174095 )

• severe reduction at age P21 and P120

• normal at age P7

thin retina outer nuclear layer ( J:174095 )

• normal at age P7

• severe reduction at age P21 and P120

retina outer nuclear layer degeneration ( J:174095 )

• much thinner at age P21

• rosette structures at age P21

• complete loss of photoreceptor cells in some parts at age P120

• increased apoptosis at age P21

• normal levels of apoptosis between ages E16 and P7

retina degeneration ( J:174095 )

• much thinner at age P21

• rosette structures in outer nuclear layer (ONL) at age P21

• absence of optic nerve fiber layer/inner limiting membrane layer (NFL/ILML) at age P21

• complete loss of photoreceptor cells in some parts of ONL at age P120

• increased apoptosis from age P10

• 50% reduction in all retinal neurons and Mueller glia cells at age P21

• reactive gliosis of Mueller glia cells at age P21

• normal levels of apoptosis between ages E16 and P7

decreased a-wave amplitude ( J:174095 )

• with scotopic ERG using very bright flashes at age 3 months

decreased b-wave amplitude ( J:174095 )

• with scotopic ERG using dim flashes at age 3 months

• with photopic ERG using double flashes at age 3 months

abnormal cone electrophysiology ( J:174095 )

• significantly reduced b wave amplitude with photopic ERG using double flashes at age 3 months

abnormal rod electrophysiology ( J:174095 )

• significantly reduced saturated a wave amplitude with scotopic ERG using very bright flashes at age 3 months

nervous system

retina ganglion cell degeneration ( J:174095 )

• increased apoptosis at age P10

• normal levels of apoptosis between ages E16 and P7

optic nerve atrophy ( J:174095 )

• much thinner and with numerous vacuoles at age P21

Genotype
MGI:6384015

cn8

• Allelic Composition: Ptpn11^tm1Gsf/Ptpn11^tm1Gsf; Stat3^tm1Xyfu/Stat3^tm1Xyfu; Tg(Six3-cre)69Frty/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2

vision/eye

retina ganglion cell degeneration ( J:174095 )

• much thinner at age P21, more severe than in mice with wildtype Stat3 allele

thin retina ganglion layer ( J:174095 )

• severe reduction at age P21, more severe than in mice with wildtype Stat3 allele

thin retina inner nuclear layer ( J:174095 )

• severe reduction at age P21, more severe than in mice with wildtype Stat3 allele

thin retina outer nuclear layer ( J:174095 )

• severe reduction at age P21, more severe than in mice with wildtype Stat3 allele

retina outer nuclear layer degeneration ( J:174095 )

• much thinner at age P21, more severe than in mice with wildtype Stat3 allele

thin retina outer plexiform layer ( J:174095 )

• largely disappeared at age P21, more severe than in mice with wildtype Stat3 allele

retina degeneration ( J:174095 )

• much thinner at age P21, more severe than in mice with wildtype Stat3 allele

nervous system

retina ganglion cell degeneration ( J:174095 )

• much thinner at age P21, more severe than in mice with wildtype Stat3 allele

Genotype
MGI:7281502

cn9

• Allelic Composition: Ptpn11^tm1Gsf/Ptpn11^tm1Gsf; Plekha5^{Tg(AMH-cre)1Flor}/Plekha5⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL

reproductive system

abnormal spermatocyte morphology ( J:250152 )

♂ • number of SYCP3+ spermatocytes is significantly increased at 1 week but significantly decreased at 3 weeks of age

abnormal spermatogonia morphology ( J:250152 )

♂ • number of PLZF+ undifferentiated spermatogonial stem cells (SSCs) is normal at 1 week of age but significantly reduced at 2-, 3- and 4 weeks of age

♂ • unlike in controls where Kit (a differentiated SSC marker ) is first expressed at ~P6 and reaches a high level at 2 weeks of age, strong Kit signals are noted at P3 and at 1 week but are degraded by 2 weeks, suggesting untimely and excessive SSC differentiation

♂ • number of STRA8+ differentiated SSCs is significantly increased at 1 week but gradually reduced in the disrupted tubule starting at 3 weeks of age

♂ • when wild-type SSCs are seeded on primary Sertoli cells isolated from 2-week-old mutant males, clone formation ability of SSCs is impaired

♂ • adenovirus infection with a constitutively active Shp2 mutant rescues the capacity of wild-type SSCs to form clones

decreased male germ cell number ( J:250152 )

♂ • testes show gradual loss of the germ cells resulting in Sertoli cell-only phenotype

♂ • ~31% of seminiferous tubules have lost all of the germ cells by 16 weeks of age

azoospermia ( J:250152 )

♂ • no mature sperm are found in the edidymides at 8 weeks of age

increased male germ cell apoptosis ( J:250152 )

♂ • at 4 weeks of age, testes contain significantly more TUNEL+ apoptotic cells than control testes

♂ • however, the number of WT1+ Sertoli cells is normal

abnormal seminiferous tubule epithelium morphology ( J:250152 )

♂ • at 3 weeks of age, the number of cells in the seminiferous tubule epithelium is decreased and cells exhibit a disordered arrangement

abnormal Sertoli cell barrier morphology ( J:250152 )

♂ • at 2 weeks of age, junction proteins critical for original BTB assembly, including GJA1 (connexin 43), CLDN11 (claudin 11) and F11R (aka JAMA), show aberrant localization and are dispersed over the seminiferous tubules, instead of being arranged in a regular cycle between the basal and adluminal compartments as in control tubules

♂ • CLDN11 and GJA1 protein expression is significantly increased whereas F11R expression is significantly reduced

♂ • when primary Sertoli cells from 2-wk-old males are cultured in vitro, transepithelial electrical resistance values of the Sertoli cell monolayer fail to increase with cell growth and, unlike in control cells, do not reach a peak level on day 3, indicating impaired cell junctions

♂ • adenovirus infection with a constitutively active Shp2 mutant rescues the tight junction defects and restores electrical resistance peak level on day 3

small seminiferous tubules ( J:250152 )

♂ • seminiferous tubules become significantly thinner by 16 weeks of age

seminiferous tubule degeneration ( J:250152 )

♂ • at 4 weeks of age, 84% of seminiferous tubules appear damaged and show cell loss, vacuolization, a chaotic arrangement of germ cells, and absence of elongated sperm

♂ • by 16 weeks of age, tubules are severely destroyed; ~31% of tubules have lost all of the germ cells, become significantly thinner and contain only Sertoli cells

increased Leydig cell number ( J:250152 )

♂ • Leydig cell hyperplasia is observed by 16 weeks of age

decreased testis weight ( J:250152 )

♂ • average weight of testes is significantly lower than in controls males at 2-, 3- and 4 weeks of age

♂ • however, body weight is normal

abnormal Sertoli cell barrier function ( J:250152 )

♂ • at 2 weeks of age, an in vivo biotin tracing assay showed that the tracer dye penetrates into the adluminal compartment in 77% of seminiferous tubules, suggesting increased BTB permeability

arrest of spermatogenesis ( J:250152 )

♂ • the initial stage of spermatogenesis is blocked, and germ cells are depleted due to excessive spermatogonial stem cell (SSC) differentiation

male infertility ( J:250152 )

♂ • when mated with wild-type females, adult male mice do not produce any progeny despite normal vaginal plug formation

cellular

abnormal spermatocyte morphology ( J:250152 )

♂ • number of SYCP3+ spermatocytes is significantly increased at 1 week but significantly decreased at 3 weeks of age

abnormal spermatogonia morphology ( J:250152 )

♂ • number of PLZF+ undifferentiated spermatogonial stem cells (SSCs) is normal at 1 week of age but significantly reduced at 2-, 3- and 4 weeks of age

♂ • unlike in controls where Kit (a differentiated SSC marker ) is first expressed at ~P6 and reaches a high level at 2 weeks of age, strong Kit signals are noted at P3 and at 1 week but are degraded by 2 weeks, suggesting untimely and excessive SSC differentiation

♂ • number of STRA8+ differentiated SSCs is significantly increased at 1 week but gradually reduced in the disrupted tubule starting at 3 weeks of age

♂ • when wild-type SSCs are seeded on primary Sertoli cells isolated from 2-week-old mutant males, clone formation ability of SSCs is impaired

♂ • adenovirus infection with a constitutively active Shp2 mutant rescues the capacity of wild-type SSCs to form clones

decreased male germ cell number ( J:250152 )

♂ • testes show gradual loss of the germ cells resulting in Sertoli cell-only phenotype

♂ • ~31% of seminiferous tubules have lost all of the germ cells by 16 weeks of age

azoospermia ( J:250152 )

♂ • no mature sperm are found in the edidymides at 8 weeks of age

increased male germ cell apoptosis ( J:250152 )

♂ • at 4 weeks of age, testes contain significantly more TUNEL+ apoptotic cells than control testes

♂ • however, the number of WT1+ Sertoli cells is normal

endocrine/exocrine glands

abnormal seminiferous tubule epithelium morphology ( J:250152 )

♂ • at 3 weeks of age, the number of cells in the seminiferous tubule epithelium is decreased and cells exhibit a disordered arrangement

abnormal Sertoli cell barrier morphology ( J:250152 )

♂ • at 2 weeks of age, junction proteins critical for original BTB assembly, including GJA1 (connexin 43), CLDN11 (claudin 11) and F11R (aka JAMA), show aberrant localization and are dispersed over the seminiferous tubules, instead of being arranged in a regular cycle between the basal and adluminal compartments as in control tubules

♂ • CLDN11 and GJA1 protein expression is significantly increased whereas F11R expression is significantly reduced

♂ • when primary Sertoli cells from 2-wk-old males are cultured in vitro, transepithelial electrical resistance values of the Sertoli cell monolayer fail to increase with cell growth and, unlike in control cells, do not reach a peak level on day 3, indicating impaired cell junctions

♂ • adenovirus infection with a constitutively active Shp2 mutant rescues the tight junction defects and restores electrical resistance peak level on day 3

small seminiferous tubules ( J:250152 )

♂ • seminiferous tubules become significantly thinner by 16 weeks of age

seminiferous tubule degeneration ( J:250152 )

♂ • at 4 weeks of age, 84% of seminiferous tubules appear damaged and show cell loss, vacuolization, a chaotic arrangement of germ cells, and absence of elongated sperm

♂ • by 16 weeks of age, tubules are severely destroyed; ~31% of tubules have lost all of the germ cells, become significantly thinner and contain only Sertoli cells

increased Leydig cell number ( J:250152 )

♂ • Leydig cell hyperplasia is observed by 16 weeks of age

decreased testis weight ( J:250152 )

♂ • average weight of testes is significantly lower than in controls males at 2-, 3- and 4 weeks of age

♂ • however, body weight is normal

abnormal Sertoli cell barrier function ( J:250152 )

♂ • at 2 weeks of age, an in vivo biotin tracing assay showed that the tracer dye penetrates into the adluminal compartment in 77% of seminiferous tubules, suggesting increased BTB permeability

Genotype
MGI:7281516

cn10

• Allelic Composition: Ptpn11^tm1Gsf/Ptpn11^tm1Gsf; Tg(Inha-cre)3Zuk/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL

reproductive system

seminiferous tubule degeneration ( J:250152 )

♂ • tubules exhibit a damaged structure by 8 weeks of age

small testis ( J:250152 )

♂ • at 3 weeks of age, testes are significantly smaller than those in control males

arrest of spermatogenesis ( J:250152 )

♂

male infertility ( J:250152 )

♂

endocrine/exocrine glands

seminiferous tubule degeneration ( J:250152 )

♂ • tubules exhibit a damaged structure by 8 weeks of age

small testis ( J:250152 )

♂ • at 3 weeks of age, testes are significantly smaller than those in control males

Genotype
MGI:4943280

cn11

• Allelic Composition: Ptpn11^tm1Gsf/Ptpn11^tm1Gsf; Tg(Pax6-cre,GFP)1Pgr/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * FVB

endocrine/exocrine glands

abnormal lacrimal gland development ( J:130571 )

• at E14.5 and P0, lacrimal gland development is disrupted compared to in wild-type mice

absent lacrimal glands ( J:130571 )

vision/eye

abnormal lacrimal gland development ( J:130571 )

• at E14.5 and P0, lacrimal gland development is disrupted compared to in wild-type mice

absent lacrimal glands ( J:130571 )

Genotype
MGI:5906203

cn12

• Allelic Composition: Ptpn11^tm1Gsf/Ptpn11^tm1Gsf; Tg(Ckmm-cre)5Khn/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * FVB

growth/size/body

enlarged heart ( J:144767 )

♂ • 66% increase in heart/body weight ratios

mortality/aging

premature death ( J:144767 )

• mice begin to die within 2 weeks after birth and have a median survival age of 13.4 weeks, with very few living up to 36 weeks

cardiovascular system

increased cardiac muscle triglyceride level ( J:144767 )

• elevation in levels of triglyceride in the heart

• however, no differences in glycogen content of cardiac muscle

increased myocardial fiber size ( J:144767 )

♂ • cardiomyocyte capacitance, a measure of cell size, is augmented, with cells showing a 2-fold increase in capacitance

enlarged heart ( J:144767 )

♂ • 66% increase in heart/body weight ratios

increased heart ventricle size ( J:144767 )

♂

dilated cardiomyopathy ( J:144767 )

♂ • enlarged right and left ventricle chambers with thinner walls

♂ • however, fibrosis, changes in apoptosis or proliferation,or lymphocyte and macrophage infiltration in the heart are not seen

decreased cardiac muscle cell glucose uptake ( J:144767 )

♂ • glucose uptake is impaired in cardiac muscle cells

decreased heart left ventricle muscle contractility ( J:144767 )

♂ • decrease in left ventricular fraction shortening and the velocity of circumferential fiber shortening

abnormal heart echocardiography feature ( J:144767 )

♂ • enlarged left ventricular chamber size in 6 week old mice, increase in left ventricular internal dimension at end diastole and end systole, and significant wall thinning as evidenced by decrease in systolic dimensions in interventricular septal wall thickness

♂ • however, no change in left ventricular posterior wall thickness is seen

abnormal myocardial fiber calcium currents ( J:144767 )

♂ • cardiomyocytes exhibit slower calcium current density (inward current amplitude normalized to cell capacitance)

congestive heart failure ( J:144767 )

♂

cellular

decreased cardiac muscle cell glucose uptake ( J:144767 )

♂ • glucose uptake is impaired in cardiac muscle cells

decreased skeletal muscle cell glucose uptake ( J:144767 )

♂ • glucose uptake is impaired in skeletal muscle cells

homeostasis/metabolism

increased cardiac muscle triglyceride level ( J:144767 )

• elevation in levels of triglyceride in the heart

• however, no differences in glycogen content of cardiac muscle

increased circulating insulin level ( J:144767 )

♂ • circulating insulin levels under fed and fasted conditions are slightly increased

increased circulating triglyceride level ( J:144767 )

• elevation in levels of triglyceride in plasma

• however, no differences in circulating free fatty acids

impaired glucose tolerance ( J:144767 )

• glucose intolerance, with the most significant difference seen at 120 min after glucose injection

insulin resistance ( J:144767 )

• males and females show a decreased ability to lower circulating glucose levels after intraperitoneal injection of insulin

increased skeletal muscle triglyceride level ( J:144767 )

• elevation in levels of triglyceride in skeletal muscle

• however, no differences in glycogen content of skeletal muscle

muscle

increased cardiac muscle triglyceride level ( J:144767 )

• elevation in levels of triglyceride in the heart

• however, no differences in glycogen content of cardiac muscle

increased myocardial fiber size ( J:144767 )

♂ • cardiomyocyte capacitance, a measure of cell size, is augmented, with cells showing a 2-fold increase in capacitance

dilated cardiomyopathy ( J:144767 )

♂ • enlarged right and left ventricle chambers with thinner walls

♂ • however, fibrosis, changes in apoptosis or proliferation,or lymphocyte and macrophage infiltration in the heart are not seen

decreased cardiac muscle cell glucose uptake ( J:144767 )

♂ • glucose uptake is impaired in cardiac muscle cells

decreased heart left ventricle muscle contractility ( J:144767 )

♂ • decrease in left ventricular fraction shortening and the velocity of circumferential fiber shortening

decreased skeletal muscle cell glucose uptake ( J:144767 )

♂ • glucose uptake is impaired in skeletal muscle cells

increased skeletal muscle triglyceride level ( J:144767 )

• elevation in levels of triglyceride in skeletal muscle

• however, no differences in glycogen content of skeletal muscle

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
dilated cardiomyopathy		DOID:12930	OMIM:PS115200	J:144767
disease of metabolism		DOID:0014667		J:144767