Phenotypes associated with this allele

• Allele Symbol: Tgfb1^tm1N
• Allele Name: targeted mutation 1, National Institutes of Health
• Allele ID: MGI:1857671
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Tgfb1^tm1N/Tgfb1^tm1N	involves: 129S/SvEv	MGI:2174772
hm2	Tgfb1^tm1N/Tgfb1^tm1N	involves: 129S/SvEv * C57BL/6J * NIH/Ola	MGI:3688443
ht3	Tgfb1^tm1N/Tgfb1^+	involves: 129S/SvEv * C57BL/6J * NIH/Ola	MGI:3688444
cx4	Fbn1^Tsk/Fbn1^+ Tgfb1^tm1N/Tgfb1^+	involves: 129S/SvEv * C57BL/6J * C57BL/10 * DBA/2	MGI:3800678
cx5	Fbn1^Tsk/Fbn1^+ Tgfb1^tm1N/Tgfb1^tm1N	involves: 129S/SvEv * C57BL/6J * C57BL/10 * DBA/2	MGI:3800993

Genotype
MGI:2174772

hm1

• Allelic Composition: Tgfb1^tm1N/Tgfb1^tm1N
• Genetic Background: involves: 129S/SvEv

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

Histopathological analysis on lung and heart tissues of Tgfb1^tm1N/Tgfb1^tm1N mice

mortality/aging

premature death ( J:50848 )

• wasted homozygotes die by 3-4 weeks of age due to severe cardiac and pulmonary pathology

prenatal lethality, incomplete penetrance ( J:50848 )

• at birth, homozygotes are obtained at a reduced Mendelian frequency (10% vs expected 25%), suggesting significant embryonic loss

growth/size/body

cachexia ( J:50848 )

• homozygotes start loosing weight after P10-P14; by P21, their body weight is ~50% that of wild-type mice

immune system

absent Langerhans cell ( J:120085 )

abnormal immune system physiology ( J:120085 )

• diffuse infiltrate is present in the heart

• in the lung, inflammatory lesions are usually localized to bronchi and larger vessels and sometimes diffusely within the alveolar walls

• inflammation lesions in the liver are localized to the portal canal

increased inflammatory response ( J:50848 )

• homozygotes exhibit a massive inflammatory response with abundant infiltration of lymphocytes and macrophages (but not neutrophils) in many organs, but mainly in the heart and lungs

• all (14 of 14) homozygotes display heart and pulmonary lesions; involvement of other organs is variable between individual mice

• no significant lesions are observed in the small intestine, thymus, most connective tissues, brain, skin or bone marrow

phlebitis ( J:50848 )

• at P10-P21, all homozygotes display severe pulmonary vasculitis (phlebitis) with perivascular cuffing

• 2 of 14 homozygotes exhibit rare syncytial bronchial epithelial cells

atrial endocarditis ( J:50848 )

• at P10-P21, all homozygotes display atrial endocarditis

myocarditis ( J:50848 )

• at P10-P21, all homozygotes display myocarditis, with mononuclear inflammatory cells including some syncytial cells

pericarditis ( J:50848 )

• at P10-P21, some homozygotes display pericarditis

salivary gland inflammation ( J:50848 )

• at P10-P21, several homozygotes display sialoadenitis

pancreas inflammation ( J:50848 )

• at P10-P21, 2 of 14 homozygotes exhibit vascular and inflammatory focal lesions in pancreas

lymph node inflammation ( J:50848 )

• at P10-P21, homozygotes display inflammatory lesions in the mediastinal lymph nodes, with increased proliferation of immunoblasts and lymphoblasts in B- and T-cell zones

interstitial pneumonia ( J:50848 )

• at P10-P21, all homozygotes display interstitial pneumonia

cardiovascular system

phlebitis ( J:50848 )

• at P10-P21, all homozygotes display severe pulmonary vasculitis (phlebitis) with perivascular cuffing

• 2 of 14 homozygotes exhibit rare syncytial bronchial epithelial cells

atrial endocarditis ( J:50848 )

• at P10-P21, all homozygotes display atrial endocarditis

myocarditis ( J:50848 )

• at P10-P21, all homozygotes display myocarditis, with mononuclear inflammatory cells including some syncytial cells

pericarditis ( J:50848 )

• at P10-P21, some homozygotes display pericarditis

digestive/alimentary system

colonic necrosis ( J:50848 )

• at P10-P21, some homozygotes display mild colonic necrosis

gastric necrosis ( J:50848 )

• at P10-P21, some homozygotes display mild gastic necrosis

salivary gland inflammation ( J:50848 )

• at P10-P21, several homozygotes display sialoadenitis

respiratory system

interstitial pneumonia ( J:50848 )

• at P10-P21, all homozygotes display interstitial pneumonia

abnormal lung morphology ( J:120085 )

• in the lung, inflammatory lesions are usually localized to bronchi and larger vessels and sometimes diffusely within the alveolar walls

endocrine/exocrine glands

salivary gland inflammation ( J:50848 )

• at P10-P21, several homozygotes display sialoadenitis

pancreas inflammation ( J:50848 )

• at P10-P21, 2 of 14 homozygotes exhibit vascular and inflammatory focal lesions in pancreas

homeostasis/metabolism

abnormal atrial thrombosis ( J:50848 )

• at P10-P21, some homozygotes display atrial thrombosis

hematopoietic system

absent Langerhans cell ( J:120085 )

liver/biliary system

abnormal liver morphology ( J:120085 )

• inflammation lesions in the liver are localized to the portal canal

integument

disheveled coat ( J:50848 )

• wasting homozygotes display a disheveled appearance

cellular

colonic necrosis ( J:50848 )

• at P10-P21, some homozygotes display mild colonic necrosis

gastric necrosis ( J:50848 )

• at P10-P21, some homozygotes display mild gastic necrosis

Genotype
MGI:3688443

hm2

• Allelic Composition: Tgfb1^tm1N/Tgfb1^tm1N
• Genetic Background: involves: 129S/SvEv * C57BL/6J * NIH/Ola

mortality/aging

lethality throughout fetal growth and development, incomplete penetrance ( J:26913 )

• a number of resorptions are also noted between E11.5 and E18.5

postnatal lethality ( J:68448 )

postnatal lethality, incomplete penetrance ( J:26913 )

• most homozygotes that survive the prenatal period die by 3 weeks after birth; one female homozygote survived to 7 weeks

embryonic lethality during organogenesis, incomplete penetrance ( J:26913 )

• 50% of homozygotes die between E9.5 and E11.5

• 2 of 5 homozygous embryos conceived by a homozygous mutant mother died at ~E9.5 while 3 were still alive but harvested at E12.5 due to poor health of the mother

embryo

embryo tissue necrosis ( J:26913 )

• at E9.5 and E10.5, some homozygotes display evidence of necrosis

embryonic growth retardation ( J:26913 )

• at E9.5, most embryos with yolk sac defects are slightly growth retarded by ~0.5 days

• at E10.5, severely affected mutant embryos approximate E8.5 wild-type embryos

open neural tube ( J:26913 )

• 1 of 5 mutant embryos conceived by a homozygous mutant mother is still alive at E12.5 but shows a twisted, open neural tube, several cardiac defects and delayed hepatic development

abnormal extraembryonic tissue morphology ( J:26913 )

• at E9.5-E10.5, ~50% of homozygotes show specific defects in extraembryonic tissues of the yolk sac and allantois/umbilical cord

• however, no cardiovascular anomalies (e.g. vascular dilation or loss of endothelial integrity) or fetal liver defects are noted up to E9.5

abnormal vitelline vasculature morphology ( J:26913 )

• at E9.5, 8 of 22 homozygotes show isolated defects in yolk sac vasculogenesis, with variable severiry; 5 display a combination of both vascular and hematopoietic defects

• defects range from a delay in vasculogenesis to development of small and disorganized delicate vessels to complete absence of vitelline vessels in severe cases

• notably, 3 of 5 homozygous embryos conceived by a homozygous mutant mother are still alive at E12.5 but show severely reduced vascular networks in their yolk sacs

absent vitelline blood vessels ( J:26913 )

• at E9.5-E10.5, severely affected homozygotes show absence of vitelline blood vessels

pale yolk sac ( J:26913 )

• at E10.5, mutant yolk sacs exhibit variable extents of anemia

abnormal embryonic hematopoiesis ( J:26913 )

• at E9.5, 9 of 22 homozygotes exhibit isolated hematopoietic defects, 8 show isolated vascular defects, and 5 show a combination of both

abnormal embryonic erythropoiesis ( J:26913 )

• at E9.5, mutant embryos with yolk sac anemia show up to a 90% reduction in erythroid cell number

• however, no endothelial or hematopoietic hyperplasia is observed

failure of chorioallantoic fusion ( J:26913 )

• in some cases, the allantois fails to fuse with the chorion

hematopoietic system

abnormal embryonic hematopoiesis ( J:26913 )

• at E9.5, 9 of 22 homozygotes exhibit isolated hematopoietic defects, 8 show isolated vascular defects, and 5 show a combination of both

abnormal embryonic erythropoiesis ( J:26913 )

• at E9.5, mutant embryos with yolk sac anemia show up to a 90% reduction in erythroid cell number

• however, no endothelial or hematopoietic hyperplasia is observed

growth/size/body

embryonic growth retardation ( J:26913 )

• at E9.5, most embryos with yolk sac defects are slightly growth retarded by ~0.5 days

• at E10.5, severely affected mutant embryos approximate E8.5 wild-type embryos

homeostasis/metabolism

edema ( J:26913 )

• at E9.5 and E10.5, some homozygotes display evidence of edema

cardiovascular system

abnormal vascular endothelial cell differentiation ( J:26913 )

• at E9.5, defective yolk sacs show disruption of endothelial cell adhesion resulting in separation of the two endothelial layers and buckling of the endoderm

abnormal vitelline vasculature morphology ( J:26913 )

• at E9.5, 8 of 22 homozygotes show isolated defects in yolk sac vasculogenesis, with variable severiry; 5 display a combination of both vascular and hematopoietic defects

• defects range from a delay in vasculogenesis to development of small and disorganized delicate vessels to complete absence of vitelline vessels in severe cases

• notably, 3 of 5 homozygous embryos conceived by a homozygous mutant mother are still alive at E12.5 but show severely reduced vascular networks in their yolk sacs

absent vitelline blood vessels ( J:26913 )

• at E9.5-E10.5, severely affected homozygotes show absence of vitelline blood vessels

abnormal heart development ( J:26913 )

• at E12.5, 1 of 5 mutant embryos conceived by a homozygous mutant mother is alive with multiple cardiac defects while 2 show loss of cardiac ventricular lacuni; the remaining 2 die at ~E9.5

cellular

abnormal vascular endothelial cell differentiation ( J:26913 )

• at E9.5, defective yolk sacs show disruption of endothelial cell adhesion resulting in separation of the two endothelial layers and buckling of the endoderm

embryo tissue necrosis ( J:26913 )

• at E9.5 and E10.5, some homozygotes display evidence of necrosis

nervous system

open neural tube ( J:26913 )

• 1 of 5 mutant embryos conceived by a homozygous mutant mother is still alive at E12.5 but shows a twisted, open neural tube, several cardiac defects and delayed hepatic development

liver/biliary system

delayed hepatic development ( J:26913 )

• 3 of 5 mutant embryos conceived by a homozygous mutant mother are still alive at E12.5 but display retarded hepatic development

Genotype
MGI:3688444

ht3

• Allelic Composition: Tgfb1^tm1N/Tgfb1⁺
• Genetic Background: involves: 129S/SvEv * C57BL/6J * NIH/Ola

mortality/aging

embryonic lethality during organogenesis, incomplete penetrance ( J:26913 )

• 20-25% of heterozygotes die between E9.5 and E11.5

Genotype
MGI:3800678

cx4

• Allelic Composition: Fbn1^Tsk/Fbn1⁺; Tgfb1^tm1N/Tgfb1⁺
• Genetic Background: involves: 129S/SvEv * C57BL/6J * C57BL/10 * DBA/2

respiratory system

overexpanded pulmonary alveolus ( J:68448 )

• enlarged alveoli and a histologic picture of emphysema are found, similar to that seen in tight skin heterozygotes with normal TGFB1 expression

immune system

immune system phenotype ( J:68448 )

N • unlike tight skin mice, these compound mutants do not develop autoantibodies against the scleroderma antigens topoisomerase I and fibrillin 1

integument

abnormal cutaneous collagen fibril morphology ( J:68448 )

• electron micrographs of skin show a predominance of abnormally small diameter collagen fibers, the skin is slightly thicker than normal but not as thick as in tight skin mutants with normal TGFB1 expression, and the fat tissue and hair follicles are preserved

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
pulmonary emphysema		DOID:9675	OMIM:130700	J:68448

Genotype
MGI:3800993

cx5

• Allelic Composition: Fbn1^Tsk/Fbn1⁺; Tgfb1^tm1N/Tgfb1^tm1N
• Genetic Background: involves: 129S/SvEv * C57BL/6J * C57BL/10 * DBA/2

mortality/aging

prenatal lethality ( J:68448 )

• absence of tight skin heterozygous Tgfb1 null pups from several crosses of heterozygotes is indicative of embryonic loss