Mouse Genome Informatics
cx1
    Tg(GFAP-tTA)67Pop/0
Tg(tetO-Ifng)184Pop/0

B6.Cg-Tg(GFAP-tTA)67Pop Tg(tetO-Ifng)184Pop
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• if double transgenic pups receive doxycycline through gestation and postnatally, or through gestation but treatment stops at birth, animals appear healthy with no histologic lesions (J:94092)
• if pregnant mice do not receive doxycycline (dox) during gestation, >80% of pups die in the neonatal period; double transgenic animals are never recovered
• all ataxic mice (when dox treatment is stopped at E16) die at 3-4 weeks from a progressive neurological syndrome

growth/size
• if double transgenic pups receive doxycycline until E16, about 80% start to show growth retardation in the second postnatal week

tumorigenesis
• necropsy of animals dying at 3-4 weeks shows infiltrative lesions of cerebellar hemispheres composed of tumor cells (mitotically active, primitive-appearing cells with hyperchromatic nuclei and little cytoplasm)
• when affected mice start to receive dox again at P16, tumors show less necrosis and apoptosis than untreated mutants
• pups which received doxycline to birth with cessation at P0 have normal cerebellar architecture and do not show tumor formation or migration abnormalities of granule cell precursors

behavior/neurological
• if double transgenic pups receive doxycycline until E16, about 80% develop tremor around P12
• if double transgenic pups receive doxycycline until E16, about 80% develop ataxia around P12

nervous system
• tumor cells are observed primarily in the molecular layer and external granule layer, but also frequently invading the deep cerebellar white matter and brainstem structures
• at P12, mice which received doxycycline until E16 display lesions confined to the EGL which shows a diffuse hyperplasia throughout the cerebellar hemispheres
• at P16, affected animals show marked proliferation of the EGL with diffuse infiltration of the molecular layer, consistent with malignant tumor formation; in contrast, control animals exhibit complete regression of the EGL

Mouse Models of Human Disease
OMIM IDRef(s)
Medulloblastoma; MDB 155255 J:94092


Mouse Genome Informatics
cx2
    Tg(GFAP-tTA)78Pop/0
Tg(tetO-Ifng)184Pop/0

B6.Cg-Tg(GFAP-tTA)78Pop Tg(tetO-Ifng)184Pop
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• when dams are treated with doxycycline (dox) until E16, double transgenic offspring are runted postnatally and display a failure to thrive

nervous system
• modest numbers of T lymphocytes are observed scattered throughout the cerebellum of double transgenic animals that received dox treatment until E16; this is not observed in controls
• at P14, external granule layer (EGL) persists in mutants that receive dox until E16 whereas in controls the EGL is no longer present
• at P14, numerous proliferating cells are detected, as well as increased vasculature, when animals received dox until E16
• double transgenic pups which received dox during development until E16 show significant enlargement of the cerebellum at P14
• gliosis and astrocyte hypertrophy is also observed

behavior/neurological

immune system
• at P14, IFN-g protein was detectable only in lysates of cerebellum from double transgenic mice that had been released from doxycycline at E16, but not in control samples
• modest numbers of T lymphocytes are observed scattered throughout the cerebellum of double transgenic animals that received dox treatment until E16; this is not observed in controls


Mouse Genome Informatics
cx3
    Tg(GFAP-tTA)67Pop/0
Tg(tetO-Ifng)184Pop/0

involves: 129S/SvEv * C57BL/6 * DBA/2
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• when doxycycline treatment is stopped at E 16, around 90% of double mutants develop medulloblastoma and die by P21

Mouse Models of Human Disease
OMIM IDRef(s)
Medulloblastoma; MDB 155255 J:94092


Mouse Genome Informatics
cx4
    Stat1tm1Rds/Stat1tm1Rds
Tg(GFAP-tTA)67Pop/0
Tg(tetO-Ifng)184Pop/0

involves: 129S/SvEv * C57BL/6 * DBA/2
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• if doxycycline treatment is stopped at E16, pups display a milder phenotype and survive at least until 8 weeks of age (J:94092)
• no double transgenic pups are recovered if dams did not receive any doxycycline treatment

behavior/neurological
• if doxycycline treatment is stopped at E16, pups display minor ataxia at 2 weeks
• if doxycycline treatment is stopped at E16, pups display minor ataxia at 2 weeks

tumorigenesis
N
• if doxycycline treatment is stopped at E16, no tumors are observed in cerebella of adult mice (J:94092)


Mouse Genome Informatics
cx5
    Eif2ak3tm1Dron/Eif2ak3tm1Dron
Tg(GFAP-tTA)110Pop/0
Tg(tetO-Ifng)184Pop/0

involves: 129S6/SvEvTac * C57BL/6 * DBA/2 * Swiss Webster
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• pups die around P12 regardless whether dams received doxycycline to the end of gestation or until E14


Mouse Genome Informatics
cx6
    Eif2ak3tm1Dron/Eif2ak3+
Tg(GFAP-tTA)110Pop/0
Tg(tetO-Ifng)184Pop/0

involves: 129S6/SvEvTac * C57BL/6 * DBA/2 * Swiss Webster
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• greater than 90% of animals die by postnatal day 27

growth/size
• pups are significantly smaller than controls littermates when doxycycline treatment is stopped on E14

nervous system
• >60% of animals display tonic seizures
• when doxycycline treatment is stopped at E14, very few oligodendrocytes are detected in corpus callosum and cerebellum at P14
• if mice are treated with doxycycline until they reach maturity (4 weeks) and then are released from doxycycline, oligodendrocyte survival is unaffected
• in cervical spinal cord at P14, number of apoptotic oligodendrocytes is significantly greater than in controls when doxycycline treatment is stopped at E14
• >80% of axons are unmyelinated compared to 30% of spinal cord axons in double mutants on a wild-type Eif2ak3 background when doxycycline treatment is stopped at E14; in mice continuously receiving doxycycline treatment, <10% of spinal cord axons are unmyelinated
• if mice are treated with doxycycline until they reach maturity (4 weeks) and then are released from doxycycline, normal myelin is observed in the central nervous system
• level of myelin in CNS is significantly reduced at P14 compared to double transgenic mice with wild-type Eif2ak3

behavior/neurological
• severe tremors are observed
• >60% of animals display tonic seizures


Mouse Genome Informatics
cx7
    Tg(GFAP-tTA)110Pop/0
Tg(tetO-Ifng)184Pop/0

involves: 129S6/SvEvTac * C57BL/6 * DBA/2 * Swiss Webster
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• when doxycycline treatment is stopped at E14, double transgenic offspring exhibit good survival (J:99655)

behavior/neurological
• pups exhibit minor tremor
• pups exhibit minor ataxia