Phenotypes associated with this allele

• Allele Symbol: Smad3^tm1Par
• Allele Name: targeted mutation 1, Luis F Parada
• Allele ID: MGI:1857592
• Summary: 8 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Smad3^tm1Par/Smad3^tm1Par	129-Smad3^tm1Par/J	MGI:3760247
hm2	Smad3^tm1Par/Smad3^tm1Par	either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S1/Sv * 129X1/SvJ * C57BL/6)	MGI:2182638
cn3	Amhr2^tm3(cre)Bhr/Amhr2^+ Smad2^tm1Cxd/Smad2^tm1.1Mwst Smad3^tm1Par/Smad3^tm1Zuk	involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:3822485
cn4	Amhr2^tm3(cre)Bhr/Amhr2^+ Smad3^tm1Par/Smad3^tm1Zuk	involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:3822484
cx5	Rab25^tm1Jrgo/Rab25^tm1Jrgo Smad3^tm1Par/Smad3^+	129-Rab25^tm1Jrgo Smad3^tm1Par	MGI:4440865
cx6	Inha^tm1Bay/Inha^tm1Bay Smad3^tm1Par/Smad3^+	involves: 129S1/Sv * 129S7/SvEvBrd * 129X1/Sv * C57BL/6	MGI:3790432
cx7	Inha^tm1Bay/Inha^tm1Bay Smad3^tm1Par/Smad3^tm1Par	involves: 129S1/Sv * 129S7/SvEvBrd * 129X1/Sv * C57BL/6	MGI:3790431
cx8	Il6st^tm1Ern/Il6st^+ Smad3^tm1Par/Smad3^+	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:3837663

Genotype
MGI:3760247

hm1

• Allelic Composition: Smad3^tm1Par/Smad3^tm1Par
• Genetic Background: 129-Smad3^tm1Par/J

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

neoplasm

increased intestinal adenocarcinoma incidence ( J:106572 )

• mutants maintained free of the gram-negative enterohepatic bacteria Helicobacter for up to 9 months do not develop colon cancer as do mutants housed under normal conditions

• infection of mutants with Helicobacter triggers colon cancer in 50-66% of mutants; mucinous adenocarcinomas develop 5 to 30 weeks after infection

immune system

abnormal circulating interleukin-6 level ( J:175290 )

• at 24 hrs after bilateral renal ischemia reperfusion (I/R) injury (25 min in duration), homozygotes fail to exhibit a significant increase in plasma IL-6 levels, unlike similarly-treated wild-type controls

abnormal cytokine secretion ( J:175290 )

• at 24 hrs after bilateral renal ischemia reperfusion (I/R) injury, homozygotes exhibit a significant reduction in the renal expression of IL-6 and endothelin-1 mRNA, unlike similarly-treated wild-type controls

• however, expression of other cytokines known to contribute to ischemic acute kidney injury is not significantly altered

decreased interleukin-6 secretion ( J:175290 )

• at 24 hrs after bilateral renal ischemia reperfusion (I/R) injury, homozygotes exhibit a drastic reduction in renal expression of IL-6, unlike similarly-treated wild-type controls

increased inflammatory response ( J:106572 )

• colonic tissue of uninfected mutants is in a proinflammatory state as indicated by increased mRNA levels of IL-6, TNF-alpha, IFN-gamma, and IL-4, which is exacerbated by Helicobacter infection

renal/urinary system

decreased susceptibility to kidney reperfusion injury ( J:175290 )

• at 24 hrs after bilateral renal ischemia reperfusion (I/R) injury (either 22.5 or 25 min in duration), homozygotes exhibit better preservation of renal function as measured by serum BUN and creatinine levels

• renal histological injury is significantly reduced as shown by decreased acute tubular necrosis, intratubular sloughing and cast formation

homeostasis/metabolism

decreased circulating creatinine level ( J:175290 )

• at 24 hrs after bilateral renal ischemia reperfusion (I/R) injury (either 22.5 or 25 min in duration), homozygotes exhibit significantly reduced serum creatinine levels relative to wild-type controls

decreased blood urea nitrogen level ( J:175290 )

• at 24 hrs after bilateral renal ischemia reperfusion (I/R) injury (either 22.5 or 25 min in duration), homozygotes exhibit significantly reduced serum BUN levels relative to wild-type controls

abnormal circulating interleukin-6 level ( J:175290 )

• at 24 hrs after bilateral renal ischemia reperfusion (I/R) injury (25 min in duration), homozygotes fail to exhibit a significant increase in plasma IL-6 levels, unlike similarly-treated wild-type controls

decreased susceptibility to kidney reperfusion injury ( J:175290 )

• at 24 hrs after bilateral renal ischemia reperfusion (I/R) injury (either 22.5 or 25 min in duration), homozygotes exhibit better preservation of renal function as measured by serum BUN and creatinine levels

• renal histological injury is significantly reduced as shown by decreased acute tubular necrosis, intratubular sloughing and cast formation

digestive/alimentary system

increased intestinal adenocarcinoma incidence ( J:106572 )

• mutants maintained free of the gram-negative enterohepatic bacteria Helicobacter for up to 9 months do not develop colon cancer as do mutants housed under normal conditions

• infection of mutants with Helicobacter triggers colon cancer in 50-66% of mutants; mucinous adenocarcinomas develop 5 to 30 weeks after infection

Genotype
MGI:2182638

hm2

• Allelic Composition: Smad3^tm1Par/Smad3^tm1Par
• Genetic Background: either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S1/Sv * 129X1/SvJ * C57BL/6)

mortality/aging

premature death ( J:49839 )

• Background Sensitivity: decreased life span; more pronounced in the 129/Sv background than in the mixed 129/Sv and C57BL/6 background, but evident in both

neoplasm

increased intestinal adenocarcinoma incidence ( J:49839 )

• Background Sensitivity: penetrance of adenocarcinoma is about 30% on the mixed 129/Sv and C57BL/6 background and 100% on the 129/Sv background

• Background Sensitivity: mutants on the mixed background show greater variability in the time course of tumors and tumors are less aggressive and smaller than in the 129/Sv background

• a wide range of tumors are found within a single mouse, including lesions that appear to be polyps

increased metastatic potential ( J:49839 )

• evidence of metastasis to lymph nodes is seen on the 129/Sv background

growth/size/body

decreased body size ( J:49839 )

• about 20% - 30% smaller than controls

• males exhibit a greater size reduction than females

distended abdomen ( J:49839 )

• due to tumors

reproductive system

abnormal fertility/fecundity ( J:49839 )

• mice are fertile, but have reduced efficacy in producing litters

behavior/neurological

lethargy ( J:49839 )

• as mutants age beyond 18 weeks, they exhibit signs of distress that include lethargy

abnormal posture ( J:49839 )

• abnormal, rounded posture, but no associated skeletal defects

digestive/alimentary system

rectal prolapse ( J:49839 )

• Background Sensitivity: due to tumors; more pronounced on the 129/Sv background than on the mixed 129/Sv and C57BL/6 background, with 75% of mutants showing prolapse by 24 weeks of age

increased intestinal adenocarcinoma incidence ( J:49839 )

• Background Sensitivity: penetrance of adenocarcinoma is about 30% on the mixed 129/Sv and C57BL/6 background and 100% on the 129/Sv background

• Background Sensitivity: mutants on the mixed background show greater variability in the time course of tumors and tumors are less aggressive and smaller than in the 129/Sv background

• a wide range of tumors are found within a single mouse, including lesions that appear to be polyps

intestinal obstruction ( J:49839 )

• due to tumors

integument

ruffled hair ( J:49839 )

• as mutants age beyond 18 weeks, they exhibit signs of distress that include fur-ruffling

Genotype
MGI:3822485

cn3

• Allelic Composition: Amhr2^tm3(cre)Bhr/Amhr2⁺; Smad2^tm1Cxd/Smad2^tm1.1Mwst; Smad3^tm1Par/Smad3^tm1Zuk
• Genetic Background: involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * C57BL/6

cellular

decreased oocyte number ( J:142827 )

♀ • in superovulation experiments, mice ovulate half as many oocytes as wild-type mice

reproductive system

decreased oocyte number ( J:142827 )

♀ • in superovulation experiments, mice ovulate half as many oocytes as wild-type mice

abnormal ovarian follicle morphology ( J:142827 )

♀ • at 3 months, mice contain luteinizing follicles that encompass trapped oocytes unlike in wild-type mice

♀ • at 8 months, mice exhibit more severe follicular abnormalities than at 3 moths with aberrant cumulus cell-oocytes unlike in wild-type mice

decreased tertiary ovarian follicle number ( J:142827 )

♀ • at 3 months, fewer antral follicles are present compared to in wild-type ovaries

increased atretic ovarian follicle number ( J:142827 )

♀ • at 3 months, a marker of follicular atresia accumulates unlike in wild-type ovaries

abnormal cumulus expansion ( J:142827 )

♀ • treatment with pregnant mare serum gonadotropin (PMSG) induces only minimal cumulus expansion unlike in similarly treated wild-type mice and few cumulus cells attach to oocytes

♀ • in culture, cumulus cells undergo disorganized and limited expansion in response to EGF compared to similarly treated wild-type cells

♀ • in culture, cumulus cells stimulated by EGF detach from the cumulus oocyte complexes and attach to the culture plate leaving 18% of oocytes denuded unlike wild-type cells

premature ovarian failure ( J:142827 )

♀ • females exhibit reduced fertility and premature ovarian failure becoming infertile after 4 months of breeding unlike in wild-type mice

reduced female fertility ( J:142827 )

♀

decreased litter size ( J:142827 )

homeostasis/metabolism

increased circulating follicle stimulating hormone level ( J:142827 )

• at 8 months

increased circulating luteinizing hormone level ( J:142827 )

• at 8 months

mortality/aging

premature ovarian failure ( J:142827 )

♀ • females exhibit reduced fertility and premature ovarian failure becoming infertile after 4 months of breeding unlike in wild-type mice

endocrine/exocrine glands

abnormal ovarian follicle morphology ( J:142827 )

♀ • at 3 months, mice contain luteinizing follicles that encompass trapped oocytes unlike in wild-type mice

♀ • at 8 months, mice exhibit more severe follicular abnormalities than at 3 moths with aberrant cumulus cell-oocytes unlike in wild-type mice

decreased tertiary ovarian follicle number ( J:142827 )

♀ • at 3 months, fewer antral follicles are present compared to in wild-type ovaries

increased atretic ovarian follicle number ( J:142827 )

♀ • at 3 months, a marker of follicular atresia accumulates unlike in wild-type ovaries

abnormal cumulus expansion ( J:142827 )

♀ • treatment with pregnant mare serum gonadotropin (PMSG) induces only minimal cumulus expansion unlike in similarly treated wild-type mice and few cumulus cells attach to oocytes

♀ • in culture, cumulus cells undergo disorganized and limited expansion in response to EGF compared to similarly treated wild-type cells

♀ • in culture, cumulus cells stimulated by EGF detach from the cumulus oocyte complexes and attach to the culture plate leaving 18% of oocytes denuded unlike wild-type cells

premature ovarian failure ( J:142827 )

♀ • females exhibit reduced fertility and premature ovarian failure becoming infertile after 4 months of breeding unlike in wild-type mice

Genotype
MGI:3822484

cn4

• Allelic Composition: Amhr2^tm3(cre)Bhr/Amhr2⁺; Smad3^tm1Par/Smad3^tm1Zuk
• Genetic Background: involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * C57BL/6

reproductive system

reproductive system phenotype ( J:142827 )

N • mice exhibit normal reproductive morphology and physiology

Genotype
MGI:4440865

cx5

• Allelic Composition: Rab25^tm1Jrgo/Rab25^tm1Jrgo; Smad3^tm1Par/Smad3⁺
• Genetic Background: 129-Rab25^tm1Jrgo Smad3^tm1Par

Colon tumor formation and neoplasia in Rab25^tm1Jrgo/Rab25^tm1Jrgo Smad3^tm1Par/Smad3⁺ mice

digestive/alimentary system

abnormal colon morphology ( J:158733 )

• the glandular atypia results in numerous mucin-filled cysts in one proximal colon tumor

colon polyps ( J:158733 )

• aberrant or dysplastic crypts, hyperplastic lesions, and adenomatous polyps

abnormal rectum morphology ( J:158733 )

• rectal tumor lesions in 80% of the mice

increased colon adenocarcinoma incidence ( J:158733 )

• large invasive tumor lesions in the proximal colonic mucosa in 80% of the mice

• the colonic epithelial tumors extend into and through the submucosa with neoplastic glands penetrating the muscle wall

neoplasm

increased colon adenocarcinoma incidence ( J:158733 )

• large invasive tumor lesions in the proximal colonic mucosa in 80% of the mice

• the colonic epithelial tumors extend into and through the submucosa with neoplastic glands penetrating the muscle wall

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
colorectal cancer		DOID:9256	OMIM:114500	J:158733

Genotype
MGI:3790432

cx6

• Allelic Composition: Inha^tm1Bay/Inha^tm1Bay; Smad3^tm1Par/Smad3⁺
• Genetic Background: involves: 129S1/Sv * 129S7/SvEvBrd * 129X1/Sv * C57BL/6

neoplasm

increased adrenal gland tumor incidence ( J:125349 )

• gonadectomy causes adrenal tumorigenesis which is dependent on the chronically elevated gonadotropin levels that result from this manipulation

• the 50% survival rate of female mice with gonadectomies is 37.5 weeks with all mice dying of extensive adrenal tumor burden

• this survival rate is significantly longer than in mice that are homozygote for Inha^tm1Bay but which have two wild-type alleles for Smad3

increased ovary tumor incidence ( J:125349 )

♀ • tumor mass is 50% less than in mice homozygote for Inha^tm1Bay but which have two wild-type alleles for Smad3

reproductive system

increased ovary tumor incidence ( J:125349 )

♀ • tumor mass is 50% less than in mice homozygote for Inha^tm1Bay but which have two wild-type alleles for Smad3

endocrine/exocrine glands

increased adrenal gland tumor incidence ( J:125349 )

• gonadectomy causes adrenal tumorigenesis which is dependent on the chronically elevated gonadotropin levels that result from this manipulation

• the 50% survival rate of female mice with gonadectomies is 37.5 weeks with all mice dying of extensive adrenal tumor burden

• this survival rate is significantly longer than in mice that are homozygote for Inha^tm1Bay but which have two wild-type alleles for Smad3

increased ovary tumor incidence ( J:125349 )

♀ • tumor mass is 50% less than in mice homozygote for Inha^tm1Bay but which have two wild-type alleles for Smad3

Genotype
MGI:3790431

cx7

• Allelic Composition: Inha^tm1Bay/Inha^tm1Bay; Smad3^tm1Par/Smad3^tm1Par
• Genetic Background: involves: 129S1/Sv * 129S7/SvEvBrd * 129X1/Sv * C57BL/6

endocrine/exocrine glands

abnormal ovarian folliculogenesis ( J:125349 )

♀ • oocytes are surrounded by small follicles although follicular development is arrested in a similar manner to mice homozygous for just the Smad3^tm1Par allele

increased ovary tumor incidence ( J:125349 )

♀ • the rapid ovarian tumorigenesis associated with Inha^tm1Bay homozygotes is greatly attenuated when on a Smad3^tm1Par background

♀ • tumorigenesis still occurs as demonstrated by a mass of expansive stromal tissue commonly found on the periphery of the ovary

increased Sertoli cell number ( J:125349 )

♂ • some focal Sertoli cell hyperplasia is present in the testes of two month old mice though no tumors are observed

reproductive system

abnormal ovarian folliculogenesis ( J:125349 )

♀ • oocytes are surrounded by small follicles although follicular development is arrested in a similar manner to mice homozygous for just the Smad3^tm1Par allele

increased ovary tumor incidence ( J:125349 )

♀ • the rapid ovarian tumorigenesis associated with Inha^tm1Bay homozygotes is greatly attenuated when on a Smad3^tm1Par background

♀ • tumorigenesis still occurs as demonstrated by a mass of expansive stromal tissue commonly found on the periphery of the ovary

increased Sertoli cell number ( J:125349 )

♂ • some focal Sertoli cell hyperplasia is present in the testes of two month old mice though no tumors are observed

neoplasm

increased ovary tumor incidence ( J:125349 )

♀ • the rapid ovarian tumorigenesis associated with Inha^tm1Bay homozygotes is greatly attenuated when on a Smad3^tm1Par background

♀ • tumorigenesis still occurs as demonstrated by a mass of expansive stromal tissue commonly found on the periphery of the ovary

Genotype
MGI:3837663

cx8

• Allelic Composition: Il6st^tm1Ern/Il6st⁺; Smad3^tm1Par/Smad3⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

neoplasm

increased adenoma incidence ( J:100160 )

• develop antral adenomas by 13-24 weeks of age