Phenotypes associated with this allele

• Allele Symbol: Foxm1^tm1Rhc
• Allele Name: targeted mutation 1, Robert H Costa
• Allele ID: MGI:2448247
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Foxm1^tm1Rhc/Foxm1^tm1Rhc	involves: 129X1/SvJ	MGI:3522660
cn2	Foxm1^tm1Rhc/Foxm1^tm1Rhc Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129X1/SvJ * C57BL/6	MGI:4889055
cn3	Foxm1^tm1Rhc/Foxm1^tm1Rhc Tg(Pdx1-cre)89.1Dam/0	involves: 129X1/SvJ * C57BL/6 * CBA	MGI:5638149
cn4	Foxm1^tm1Rhc/Foxm1^tm1Rhc Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129X1/SvJ * C57BL/6 * DBA	MGI:3522661
cn5	Foxm1^tm1Rhc/Foxm1^tm1Rhc Tg(Alb1-cre)1Khk/0	involves: 129X1/SvJ * C57BL/6 * SJL	MGI:3522668
cn6	Foxm1^tm1Rhc/Foxm1^tm1Rhc Tg(Tek-cre)1Ywa/0	involves: 129X1/SvJ * C57BL/6 * SJL	MGI:3710341

Genotype
MGI:3522660

hm1

• Allelic Composition: Foxm1^tm1Rhc/Foxm1^tm1Rhc
• Genetic Background: involves: 129X1/SvJ

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

neoplasm

increased incidence of tumors by chemical induction ( J:89472 )

• after diethylnitrosamine (DEN) and phenobarbitol (PB) treatment, multiple hepatic adenomas were observed in liver sections from these mice at 23, 33 and 50 weeks of age

increased hepatocellular carcinoma incidence ( J:89472 )

homeostasis/metabolism

increased incidence of tumors by chemical induction ( J:89472 )

• after diethylnitrosamine (DEN) and phenobarbitol (PB) treatment, multiple hepatic adenomas were observed in liver sections from these mice at 23, 33 and 50 weeks of age

liver/biliary system

increased hepatocellular carcinoma incidence ( J:89472 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hepatocellular carcinoma		DOID:684	OMIM:114550	J:89472

Genotype
MGI:4889055

cn2

• Allelic Composition: Foxm1^tm1Rhc/Foxm1^tm1Rhc; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129X1/SvJ * C57BL/6

mortality/aging

neonatal lethality, incomplete penetrance ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 die within the first 24 hrs after birth due to respiratory failure

respiratory system

respiratory system phenotype ( J:142246 )

N • mice treated with doxycycline during postnatal period P3-P30 show no differences in overall lung morphology or expression of epithelial marker proteins relative to control littermates

pulmonary vascular congestion ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 display pulmonary congestion

abnormal lung development ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 display delayed lung maturation, as shown by reduced lung sacculation and mesenchymal thickening prior to birth (E17.5 and E18.5)

• however, branching morphogenesis and proliferation of distal respiratory epithelial cells is normal at E15.5 and E18.5

• no vascular abnormalities are detected at E18.5, as shown by normal Pecam-1 staining

• differentiation of ciliated and Clara cells in conducting airways remains normal

abnormal lung saccule morphology ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 display reduced lung sacculation prior to birth

• consistent with delayed lung maturation, peripheral lung tubules remain closed, unlike in control littermates

small lung saccule ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 display smaller peripheral saccules at E17.5 and E18.5

thick lung-associated mesenchyme ( J:142246 )

• increased mesenchymal thickness prior to birth

abnormal pulmonary alveolus epithelial cell morphology ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 show delayed differentiation of type I and type II epithelial cells

decreased type I pneumocyte number ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 display reduced numbers of squamous type I epithelial cells

• however, type I epithelial cells appear ultrastructurally normal

abnormal type II pneumocyte morphology ( J:142246 )

small alveolar lamellar bodies ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 show significantly smaller lamellar bodies in type II cells relative to control littermates

atelectasis ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 display focal atelectasis

abnormal respiratory conducting tube morphology ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 display pulmonary congestion, focal atelectasis, bronchial occlusion, and hyaline membranes lining terminal airways consistent with severe respiratory distress syndrome (RDS)

• ~18% of mice treated with doxycycline from E7.5 to E14.5 survive after birth and exhibit mild RDS with focal atelectasis

pulmonary hyaline membrane formation ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 display hyaline membranes lining the terminal airways

respiratory distress ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 display severe respiratory distress

respiratory failure ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 die within the first 24 hrs after birth due to respiratory failure

decreased surfactant secretion ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 show reduced pulmonary SP-A, SP-B, SP-C, and SP-D mRNA levels at E17.5 relative to control littermates

• SP-B mRNA is reduced to 40% of control values

cardiovascular system

pulmonary vascular congestion ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 display pulmonary congestion

Genotype
MGI:5638149

cn3

• Allelic Composition: Foxm1^tm1Rhc/Foxm1^tm1Rhc; Tg(Pdx1-cre)89.1Dam/0
• Genetic Background: involves: 129X1/SvJ * C57BL/6 * CBA

homeostasis/metabolism

abnormal glucose homeostasis ( J:111026 )

♂ • 13% of males are diabetic at 9 weeks of age

abnormal insulin secretion ( J:111026 )

♂ • total pancreatic insulin content is decreased in males at 6 and 9 weeks of age, and is only 30% of control levels at 9 weeks

impaired glucose tolerance ( J:111026 )

♂ • 29% of males develop impaired glucose tolerance at 6 weeks of age, as indicated by elevated blood glucose levels at 30, 60, 90, and 120 minutes of an intraperitoneal glucose tolerance test

♂ • 53% of males are glucose intolerant by 9 weeks of age

♂ • females, however, exhibit normal intraperitoneal glucose tolerance test

endocrine/exocrine glands

decreased pancreatic beta cell proliferation ( J:111026 )

♂ • decrease in beta-cell proliferation at 4, 6, and 9 weeks of age

abnormal exocrine pancreas morphology ( J:111026 )

♂ • in some glucose intolerant males at 6 weeks of age, the exocrine nuclei are enlarged and the islets look smaller

♂ • in 9 week old diabetic males, cysts are present in the exocrine pancreas

♂ • orientation of exocrine cells is irregular and nuclei of disorganized exocrine cells are enlarged in 9 week old diabetic males

abnormal pancreatic islet morphology ( J:111026 )

♂ • at 9 weeks of age, pancreas from diabetic males shows alteration in islet architecture, with a decrease in insulin-producing cells, an increase in alpha-cells and scattering of alpha-cells throughout the islets rather than at the periphery

♂ • pancreas from males with impaired glucose tolerance or diabetes shows an increase in intra-islet keratin-positive cells, suggesting that islets contain cells with a ductal phenotype

increased pancreatic alpha cell number ( J:111026 )

♂ • at 9 weeks of age, pancreas from diabetic males shows an increase in alpha-cells

abnormal pancreatic beta cell morphology ( J:111026 )

♂ • although the average beta-cell size per pancreas is the same as in controls at 9 weeks, the average beta-cell size per islet is variable, with some islets composed mainly of beta-cells that are much larger than the average and others composed of beta-cells less than 60 um², indicating that some beta-cells are undergoing hypertrophy and others are dying

decreased pancreatic beta cell mass ( J:111026 )

• decrease in beta-cell mass is seen at 4, 6, and 9 weeks of age compared to controls: mice show an initial increase in beta-cell mass from P1 to 4 weeks of age and thereafter remain the same or slightly decreased compared to controls which show continued beta cell mass increase from P1 to 9 weeks

• beta-cell mass of males is only about 30% of controls at 9 weeks of age

• females show an approximate 20% decrease in beta-cell mass at 9 weeks of age

decreased pancreatic beta cell number ( J:111026 )

♂ • pancreas from males show a gradual loss of insulin-producing cells

small pancreatic islets ( J:111026 )

• islet size in both males and females is smaller than controls at 9 weeks of age

decreased pancreas weight ( J:111026 )

♂ • whole pancreatic wet weights are slightly but significantly lower in males at 9 weeks of age

pancreas cyst ( J:111026 )

♂ • in 9 week old diabetic males, cysts are present in the exocrine pancreas; cysts are negative for oil red O staining indicating that they are not adipose accumulations and are most likely due to necrotic cell death

pancreas necrosis ( J:111026 )

♂ • exocrine tissue from diabetic males shows many enlarged cells undergoing lysis and losing membrane integrity, signs of cellular necrosis

abnormal insulin secretion ( J:111026 )

♂ • total pancreatic insulin content is decreased in males at 6 and 9 weeks of age, and is only 30% of control levels at 9 weeks

cellular

decreased pancreatic beta cell proliferation ( J:111026 )

♂ • decrease in beta-cell proliferation at 4, 6, and 9 weeks of age

digestive/alimentary system

abnormal exocrine pancreas morphology ( J:111026 )

♂ • in some glucose intolerant males at 6 weeks of age, the exocrine nuclei are enlarged and the islets look smaller

♂ • in 9 week old diabetic males, cysts are present in the exocrine pancreas

♂ • orientation of exocrine cells is irregular and nuclei of disorganized exocrine cells are enlarged in 9 week old diabetic males

growth/size/body

pancreas cyst ( J:111026 )

♂ • in 9 week old diabetic males, cysts are present in the exocrine pancreas; cysts are negative for oil red O staining indicating that they are not adipose accumulations and are most likely due to necrotic cell death

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:111026

Genotype
MGI:3522661

cn4

• Allelic Composition: Foxm1^tm1Rhc/Foxm1^tm1Rhc; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129X1/SvJ * C57BL/6 * DBA

neoplasm

decreased incidence of tumors by chemical induction ( J:89472 )

• after diethylnitrosamine (DEN) and phenobarbitol (PB) treatment, no adenomas were observed in liver sections from these mice at 23, 33 and 50 weeks of age in contrast to controls

decreased liver tumor incidence ( J:89472 )

• after diethylnitrosamine (DEN) and phenobarbitol (PB) treatment, no adenomas were observed in liver sections from these mice at 23, 33 and 50 weeks of age in contrast to controls

liver/biliary system

abnormal hepatocyte morphology ( J:81015 , J:89472 )

• hepatocyte hypertrophy and compensatory increase in liver size at 7 days after partial hepatectomy (J:81015)

• hypertrophy of hepatocytes was observed at 23 weeks after diethylnitrosamine (DEN) and phenobarbitol (PB) treatment; hepatocytes exhibited a significant reduction in DNA replication and mitosis (J:89472)

decreased liver tumor incidence ( J:89472 )

• after diethylnitrosamine (DEN) and phenobarbitol (PB) treatment, no adenomas were observed in liver sections from these mice at 23, 33 and 50 weeks of age in contrast to controls

abnormal liver regeneration ( J:81015 )

• after partial hepatectomy, hepatocytes exhibited a significant reduction in DNA replication and mitosis; changes in expression levels of cell cycle proteins were observed

homeostasis/metabolism

decreased incidence of tumors by chemical induction ( J:89472 )

• after diethylnitrosamine (DEN) and phenobarbitol (PB) treatment, no adenomas were observed in liver sections from these mice at 23, 33 and 50 weeks of age in contrast to controls

Genotype
MGI:3522668

cn5

• Allelic Composition: Foxm1^tm1Rhc/Foxm1^tm1Rhc; Tg(Alb1-cre)1Khk/0
• Genetic Background: involves: 129X1/SvJ * C57BL/6 * SJL

mortality/aging

lethality throughout fetal growth and development, incomplete penetrance ( J:94883 )

• 40% were dead by E14.5 and 70% were dead by E15.5; some animals survived until birth; heterogeneity of cre recombinase activity is suggested to result in these variable phenotypes

cellular

abnormal cell cycle ( J:94883 )

• decrease in BrdU incorporation without increase in apoptosis suggesting a block in mitosis

liver/biliary system

abnormal liver sinusoid morphology ( J:94883 )

• disruption in the organization of liver sinusoids; variable penetrance

abnormal intrahepatic bile duct morphology ( J:94883 )

• abnormal development of the intrahepatic bile ducts

abnormal hepatoblast morphology ( J:94883 )

• presence of abnormal hepatoblast cells with enlarged polyploid nuclei

• decrease in BrdU incorporation without increase in apoptosis suggesting a block in mitosis

decreased hepatoblast number ( J:94883 )

• reduced numbers of hepatoblasts; 50% reduction in the number of hepatoblasts compared to controls, but no decrease in overall size of liver suggesting a hypertrophy of remaining hepatoblasts

abnormal hepatic cord morphology ( J:94883 )

• disruption in the organization of hepatic cords; variable penetrance

cardiovascular system

abnormal liver sinusoid morphology ( J:94883 )

• disruption in the organization of liver sinusoids; variable penetrance

abnormal hepatic vein morphology ( J:94883 )

• reduction in the number of large hepatic veins; variable penetrance

endocrine/exocrine glands

abnormal intrahepatic bile duct morphology ( J:94883 )

• abnormal development of the intrahepatic bile ducts

Genotype
MGI:3710341

cn6

• Allelic Composition: Foxm1^tm1Rhc/Foxm1^tm1Rhc; Tg(Tek-cre)1Ywa/0
• Genetic Background: involves: 129X1/SvJ * C57BL/6 * SJL

mortality/aging

lethality during fetal growth through weaning, incomplete penetrance ( J:119481 )

• approximately 20% die in late gestation-postnatally

cardiovascular system

cardiovascular system phenotype ( J:119481 )

N • in the heart, no morphological defects are seen in the structure of coronary vessels and cardiac microcirculation, or in atrioventricular valves and the ventricular outflow tract and mutants have normal numbers of cardiomyocytes

abnormal lung vasculature morphology ( J:119481 )

• mutants that die exhibit vascular abnormalities in the lung

respiratory system

abnormal lung vasculature morphology ( J:119481 )

• mutants that die exhibit vascular abnormalities in the lung

lung inflammation ( J:167773 )

• mutants treated with urethane exhibit chronic lung inflammation unlike control lungs

increased lung adenoma incidence ( J:167773 )

• mutants exhibit increased numbers of lung adenomas and larger tumor diameters 30 weeks after initial urethane injection compared to controls

neoplasm

increased incidence of tumors by chemical induction ( J:167773 )

• mutants exhibit increased numbers of lung tumors (adenomas) and larger tumor diameters 30 weeks after initial urethane injection compared to controls

• mutants exhibit increased lung tumorigenesis after MCA/BHT treatment

• tumors from mutants treated with urethane exhibit increased proliferation compared to tumors from controls

increased lung adenoma incidence ( J:167773 )

• mutants exhibit increased numbers of lung adenomas and larger tumor diameters 30 weeks after initial urethane injection compared to controls

immune system

lung inflammation ( J:167773 )

• mutants treated with urethane exhibit chronic lung inflammation unlike control lungs

homeostasis/metabolism

increased incidence of tumors by chemical induction ( J:167773 )

• mutants exhibit increased numbers of lung tumors (adenomas) and larger tumor diameters 30 weeks after initial urethane injection compared to controls

• mutants exhibit increased lung tumorigenesis after MCA/BHT treatment

• tumors from mutants treated with urethane exhibit increased proliferation compared to tumors from controls

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
lung cancer		DOID:1324	OMIM:211980 OMIM:608935 OMIM:612571 OMIM:612593 OMIM:614210	J:167773