Mouse Genome Informatics
hm1
    Smad3tm1Cxd/Smad3tm1Cxd
B6.129S6-Smad3tm1Cxd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• neointimal hyperplasia is enhanced in response to arterial injury compared to wild-type
• intima contains more proliferating smooth muscle cells with less collagen deposition than in wild-type
• growth of intimal smooth muscle cells (SMC) is only weakly inhibited by TGF-beta in vitro compared to wild-type, however chemotaxis of SMC towards TGF-beta is normal

homeostasis/metabolism
• neointimal hyperplasia is enhanced in response to arterial injury compared to wild-type
• intima contains more proliferating smooth muscle cells with less collagen deposition than in wild-type
• growth of intimal smooth muscle cells (SMC) is only weakly inhibited by TGF-beta in vitro compared to wild-type, however chemotaxis of SMC towards TGF-beta is normal
• at 14 days after unilateral ureteral obstruction (UUO), the mutant obstructed kidney shows attenuated scar formation, and decreased renal interstitial fibrosis, inflammation and apoptosis relative to the wild-type obstructed kidney

renal/urinary system
N
• prior to unilateral ureteral obstruction (UUO), 10 -12 week-old mutant mice exhibit histologically normal kidneys and normal serum blood urea nitrogen (BUN) and creatinine levels relative to wild-type controls (J:102084)
• at 14 days after UUO, the number of TUNEL-positive tubular apoptotic cells is significantly reduced in the obstructed mutant kidney relative to that in wild-type controls
• at 14 days after UUO, the numbers of F4/80-positive interstitial macrophages, and CD4-positive and CD8-positive interstitial cells are significantly reduced in the obstructed mutant kidney relative to that in wild-type controls
• at 14 days after UUO, renal interstitial fibrosis is significantly attenuated in the obstructed mutant kidney relative to that in wild-type controls, as shown by Aniline-blue or Sirius red staining
• at 14 days after UUO, deposition of type I and type III collagens and the number of of alpha-SMA-positive interstitial myofibroblasts are significantly reduced in the obstructed mutant kidney relative to that in wild-type controls

immune system
• at 14 days after UUO, the numbers of F4/80-positive interstitial macrophages, and CD4-positive and CD8-positive interstitial cells are significantly reduced in the obstructed mutant kidney relative to that in wild-type controls

cellular
• at 14 days after UUO, the number of TUNEL-positive tubular apoptotic cells is significantly reduced in the obstructed mutant kidney relative to that in wild-type controls


Mouse Genome Informatics
hm2
    Smad3tm1Cxd/Smad3tm1Cxd
either: (involves: 129S6/SvEvTac * C57BL/6) or (involves: 129S6/SvEvTac * NIH Black Swiss)
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• the 70% of mice that suffer from growth retardation and develop a wasting syndrome, typically die between 1 and 3 months of age
• remaining 30% die between 3 and 8 months of age with a similar wasting syndrome

growth/size
• 70% are smaller than wild-type prior to weaning

immune system
• neutrophils show impaired chemotaxis to TGF-beta
• symptomatic mutants have an involuted thymus
• T cells invade normal regions of B cell development and germinal center formation in lymph nodes
• lymph node T cells from enlarged submandibular and mesenteric lymph nodes exhibit an activated phenotype with an increased number of CD62L cells
• multifocal formation of pyogenic abscesses, which are most often periorbital, periodontal, and within the wall of the stomach and the intestine
• symptomatic mutants show a reduction in the cellularity of the thymus
• absolute increase in white blood cell counts
• increased numbers of circulating neutrophils
• increased numbers of circulating monocytes
• symptomatic mutants have a small spleen
• symptomatic mutants show a reduction in the cellularity of the spleen
• symptomatic mutants have enlarged lymph nodes
• mediastinal, mandibular and mesenteric lymph nodes are enlarged in the majority of mutants; nodes display lymphoid hyperplasia, with extensive proliferation of T cells and an accumulation of plasma cells, effacing the normal node architecture
• inflammatory lesions in many organs, including the nasal mucosa, stomach, pancreas, colon and small intestine
• inflammatory lesions in the colon

hematopoietic system
• neutrophils show impaired chemotaxis to TGF-beta
• symptomatic mutants show a reduction in the cellularity of the thymus
• symptomatic mutants have an involuted thymus
• absolute increase in white blood cell counts
• increased numbers of circulating neutrophils
• increased numbers of circulating monocytes
• commonly see extramedullary hematopoiesis within the liver and spleen
• symptomatic mutants have a small spleen
• symptomatic mutants show a reduction in the cellularity of the spleen
• T cells invade normal regions of B cell development and germinal center formation in lymph nodes
• lymph node T cells from enlarged submandibular and mesenteric lymph nodes exhibit an activated phenotype with an increased number of CD62L cells

digestive/alimentary system
• inflammatory lesions in the colon

endocrine/exocrine glands
• symptomatic mutants show a reduction in the cellularity of the thymus
• symptomatic mutants have an involuted thymus

skeleton
• symptomatic mutants have a kyphotic posture

tumorigenesis
• rare (1 in 13 mice) development of colonic adenocardinomas in mice >6 months

cellular
• neutrophils show impaired chemotaxis to TGF-beta


Mouse Genome Informatics
hm3
    Smad3tm1Cxd/Smad3tm1Cxd
involves: 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Skeletal defects in 7 month old Smad3tm1Cxd/Smad3tm1Cxd mice

skeleton
• about 30% of P1 mutants exhibit abnormal formation of tarsal bones
• ribs are distorted due to abnormal ossification
• decrease in bone density except in areas where osteophytes form
• P40 mutants show decreased proteoglycan content in articular cartilage and growth plates
• enhancement of terminal differentiation of epiphyseal growth plate chondrocytes shortly after weaning
• synovial joint formation is normal, however mutants exhibit progressive articular cartilage degeneration
• the articular surface of joints with mild degeneration is covered with abnormally differentiated chondrocytes instead of a thin layer of resting chondrocytes
• knee joints are enlarged due to osteophytes that develop at the joint margins and within the joint space; osteophytes are also found in sternum and vertebral bone joints
• surface fibrillation (vertical cleft development) and osteophytes with varying sizes are seen in synovial cavities of most 6 month old mutants; osteophytes contain both chondrocytes and osteoblasts in the outgrowth of endochondral tissues
• abnormal calcification of the synovial joints is seen in mutants over 6 months of age
• growth plates of P21 or older mutants contain fewer proliferating chondrocytes than controls
• gradual increase in the height of the hypertrophic zone is seen in some 3-4 week old mutants and becomes more pronounced at 6-8 weeks of age
• bone rudiments from E17.5 metatarsals exhibit a diminished response to TGF-beta1 inhibition and do not show repression of hypertrophic zone expansion as is seen in controls
• progressive loss of articular cartilage leading to the development of degenerative joint disease
• formation of large osteophytes in joints

immune system
• monocytes show a selectively blunted chemotatic response to TGF-beta
• bone marrow-derived, IL-7- dependent pro-B lymphocytes fail to exhibit a TGFbeta induced increased in apoptosis following a 24 or 48 hour treatment
• progressive loss of articular cartilage leading to the development of degenerative joint disease
• formation of large osteophytes in joints

homeostasis/metabolism
• mutants show accelerated cutaneous wound healing compared with wild-type, characterized by an increased rate of re-epithelialization and reduced local infiltration of monocytes
• mutants exhibit protection against tubulointerstitial fibrosis following unilateral ureteral obstruction as evidenced by blocking of the epithelial-mesenchymal transition and abrogation of monocyte influx and collagen accumulation

renal/urinary system
• cultured primary renal tubular epithelial cells do not respond to TGF-beta1 and do not undergo the epithelial-to-mesenchymal transition (EMT) as wild-type cells and retain features of an epithelial monolayer
• cyclic mechanical stretching of mutant renal tubular epithelial cells in culture does not elicit EMT as in wild-type
• mutant epithelial cells show no phenotypic change when cocultured with monocytes unlike wild-type which show a fibroblastic appearance (exhibit EMT)

behavior/neurological
• mutants show progressive loss of movement due to degenerative joint disease

limbs/digits/tail
• about 30% of P1 mutants exhibit abnormal formation of tarsal bones
• although most of the bones in young mutants are normal, about 30% of P1 mice exhibit unilateral or bilateral angular distortion in their forelimbs due to abnormal formation of tarsal bones

integument
• primary keratinocytes in culture show reduced sensitivity to growth inhibition by TGF-beta and reduced adhesion to matrix and migration towards TGF-beta and keratinocyte growth factor

cellular
• bone marrow-derived, IL-7- dependent pro-B lymphocytes fail to exhibit a TGFbeta induced increased in apoptosis following a 24 or 48 hour treatment

hematopoietic system
• monocytes show a selectively blunted chemotatic response to TGF-beta
• bone marrow-derived, IL-7- dependent pro-B lymphocytes fail to exhibit a TGFbeta induced increased in apoptosis following a 24 or 48 hour treatment

Mouse Models of Human Disease
OMIM IDRef(s)
Osteoarthritis Susceptibility 1; OS1 165720 J:68792


Mouse Genome Informatics
hm4
    Smad3tm1Cxd/Smad3tm1Cxd
involves: 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• na´ve CD4 T cells cultured under Th17-polarizing conditions produce about 3-fold less Th17 cells
• there is also less suppression of IL-21 producing T cells under Th17 polarizing conditions

immune system
• na´ve CD4 T cells cultured under Th17-polarizing conditions produce about 3-fold less Th17 cells
• there is also less suppression of IL-21 producing T cells under Th17 polarizing conditions

homeostasis/metabolism
• homozygotes subjected to renal ischemia-reperfusion (IR) under sevoflurane anesthesia display significantly higher plasma creatinine levels than similarly treated wild-type mice
• sevoflurane fails to protect homozygotes against IR-induced renal tubular necrosis, unlike in wild-type controls
• sevoflurane also fails to protect primary cultures of renal proximal tubules against H2O2-induced necrosis, unlike in wild-type controls
• homozygotes are not protected against renal IR injury under anesthesia with sevoflurane (a volatile anesthetic), unlike similarly treated wild-type controls

renal/urinary system
• homozygotes are not protected against renal IR injury under anesthesia with sevoflurane (a volatile anesthetic), unlike similarly treated wild-type controls
• homozygotes subjected to renal IR injury under sevoflurane anesthesia exhibit more severe renal tubular necrosis than similarly treated wild-type controls
• in culture, sevoflurane-treated proximal tubule cells isolated from homozygous mutant mice are not protected against H2O2-induced necrosis, unlike similarly treated wild-type proximal tubule cells


Mouse Genome Informatics
cn5
    Smad2tm1.1Epb/Smad2tm1.1Epb
Smad3tm1Cxd/Smad3tm1Cxd
Tg(Alb-cre)21Mgn/0

involves: 129/Sv * 129S6/SvEvTac * C57BL/6 * DBA * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
liver/biliary system
N
• mice exhibit normal postnatal liver and body growth and function (J:119642)

cellular
• only a few hepatocytes attach with atypical morphology after seeding
• isolated primary hepatocytes show decreased viability immediately upon isolation, prior to plating (<70% viable cells) compared to controls or other mutant genotypes

homeostasis/metabolism
• injection of CCL4 to the liver induces a greater degree of liver injury in mice compared to control or individual single knockout mice; advanced bridging central injury is induced in livers


Mouse Genome Informatics
cx6
    Smad2tm1.1Epb/Smad2tm1.1Epb
Smad3tm1Cxd/Smad3tm1Cxd

involves: 129/Sv * 129S6/SvEvTac * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die between 1 and 8 months of age, due to primary defect in mucosal immune function

cellular
• after attachment to culture dishes, hepatocytes show relatively normal epithelial morphology but show wider cell-cell contacts and intracellular space compared to controls
• after treatment with TGFbeta, cells show little or no apoptosis, compared to control or Smad2 conditional knockout cells


Mouse Genome Informatics
cx7
    Smad2tm1Cxd/Smad2+
Smad3tm1Cxd/Smad3+

involves: 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
craniofacial
• E11 mandibular explants cultured in vitro form thinner Meckel's cartilage and show a developmental delay

skeleton
• E11 mandibular explants cultured in vitro form thinner Meckel's cartilage and show a developmental delay


Mouse Genome Informatics
cx8
    Smad2tm1Cxd/Smad2+
Smad3tm1Cxd/Smad3+

involves: 129S6/SvEvTac * NIH Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 10 of 21 E8.5-E10.5 mutants suffer lethality due to patterning defects
• lethality by E14.5 due to hepatic dysplasia

growth/size
• severely affected mutants are growth retarded at E9.5
• E14.5 mutants are somewhat larger in size

liver/biliary system
• liver architecture is distorted
• cultured livers from E10.5 mutants do not exhibit outgrowth of liver lobules with primitive bile ducts as in wild-type, instead, they suffer extensive cell death or fail to develop normal liver architecture
• dilated sinusoidal spaces
• marker analysis indicates a delay in hepatogenesis
• arrangement of hepatocytes is abnormal in E14.5 livers; hepatocytes are found in small clusters and cell plates are absent unlike in wild-type where cords of hepatocytes are distributed throughout in the parenchyma
• small livers but have the correct number of lobes and appear red
• 100% of E14.5 mutants exhibit severe liver hypoplasia (J:70388)
• liver is reduced in some mutants at E12.5-E14.5 (J:106308)
• marker analysis indicates defects in hepatoblast migration
• hepatocytes cultured in vitro fail to adhere well to various substrates, expression of beta1 integrin is lost, and E-cadherin is mislocalized, indicating that hepatocytes have abnormal adhesive properties
• liver cells are in a less proliferative state than in wild-type as indicated by PCNA antibody staining

hematopoietic system
• increase in the number of erythrocytes in E14.5 livers

craniofacial
• 20% of E14.5 mutants exhibit craniofacial defects in addition to the liver hypoplaisa (J:70388)
• some embryos display craniofacial defects as early as E8.5 (J:106308)

cardiovascular system
• dilated sinusoidal spaces
• some embryos exhibit abnormal heart looping
• some embryos exhibit an enlarged pericardiac cavity

digestive/alimentary system
• anterior ventral foregut defects at E8.5 as indicated by marker analysis, showing that the definitive endoderm fails to displace the visceral endoderm at the anterior intestinal portal

embryogenesis
• 54 of 106 mutants display patterning abnormalities of varying severity at E9.5-E10.5
• some embryos display midline defects as early as E8.5
• gastrulation defects
• definitive endoderm is reduced at E8.5 as indicated by marker analysis
• mutants display defects in the specification of hepatogenic endoderm
• severely affected mutants exhibit irregular somites at E9.5
• severely affected mutants are growth retarded at E9.5

endocrine/exocrine glands
• reduced thyroid at E10.5

nervous system
• seen in some mutants

vision/eye
• seen in some mutants

cellular
• liver cells are in a less proliferative state than in wild-type as indicated by PCNA antibody staining