Mouse Genome Informatics
cn1
    Mfn2tm1Dcc/Mfn2tm3Dcc
involves: 129 * 129S4/SvJaeSor * Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
• fibroblast derived from mutant animals exhibit Cre-dependent mitochondrial fragmentation
• loss of mtDNA nucleoids from a significant fraction of mitochondria


Mouse Genome Informatics
cn2
    Mfn1tm1Dcc/Mfn1tm2Dcc
Mfn2tm3Dcc/Mfn2+

involves: 129 * 129S4/SvJaeSor * Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
normal phenotype
• normal cerebella containing a uniform, unbroken Purkinje cell monolayer similar to that in wild-type mice at 9-week-old


Mouse Genome Informatics
cn3
    Mfn1tm1Dcc/Mfn1tm2Dcc
Mfn2tm1Dcc/Mfn2tm3Dcc
Tg(Pcp2-cre)2Mpin/0

involves: 129 * 129S4/SvJaeSor * Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• Purkinje cell death in 9 weeks-old mutant mice cerebella
• Purkinje cell dendrite attenuation in 9 weeks-old mutant mice cerebella

cellular
• decreased cytochrome C oxidase activity and increased succinate dehydrogenase activity in Purkinje cells of 9-weeks-old mutant mice indicating the electron transport chain dysfunction in mitochondria


Mouse Genome Informatics
cn4
    Mfn2tm1Dcc/Mfn2tm3Dcc
Tg(Wnt1-cre)11Rth/0

involves: 129 * 129S4/SvJaeSor * Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutant pups are born at appropriate Mendelian ratio
• after birth, about one third of mutant mice die on postnatal day 1
• all remaining mutant mice die by P17

behavior/neurological
• mice surviving beyond P1 cannot easily regain posture when placed on their backs
• mice surviving beyond P1 display uncoordinated limb movements, and move primarily by writhing on their abdomen

growth/size
• mice surviving beyond P1 are severely runted, likely due to feeding problems secondary to their movement disorder

nervous system
• severe defect in postnatal cerebellar growth


Mouse Genome Informatics
cn5
    En1tm2(cre)Wrst/En1+
Mfn2tm1Dcc/Mfn2tm3Dcc

involves: 129 * 129S4/SvJaeSor * Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutant pups are born at appropriate Mendelian ratio
• after birth, about one third of mutant mice die on postnatal day 1
• all remaining mutant mice die by P17

behavior/neurological
• mice surviving beyond P1 cannot easily regain posture when placed on their backs
• mice surviving beyond P1 display uncoordinated limb movements, and move primarily by writhing on their abdomen

growth/size
• mice surviving beyond P1 are severely runted, likely due to feeding problems secondary to their movement disorder

nervous system
• markedly higher levels of apoptosis in mutant cerebella as early as p6 and continuing through the second postnatal week
• widespread loss of Purkinje cell bodies py P15 resulting in reduction of the molecular layer
• Purkinje cell loss due to a degenerative process in mixed cerebellar cultures
• reduced growth and deterioration of Purkinje cell dendrite during the second postnatal week
• severe defect in postnatal cerebellar growth
• between P7 and P16, the mutant cerebellum reduces in size
• lobular organization and formation of the three cellular layers is relatively intact

cellular
• mitochondria in mutant Purkinje cells in mixed cerebellar cultures tend to cluster together in the cell body and do not enter the dendritic tracts
• markedly higher levels of apoptosis in mutant cerebella as early as p6 and continuing through the second postnatal week


Mouse Genome Informatics
cn6
    Mfn2tm1Dcc/Mfn2tm3Dcc
Tg(Pcp2-cre)2Mpin/0

involves: 129 * 129S4/SvJaeSor * Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• a progressive decline in coordination and balance in rotarod test
• at 2 months of age, they begin to exhibit a slightly shaky gait
• mutants are indistinguishable from wild-type littermates first 2 mo

nervous system
• obvious neuro-degeneration of cerebella over time
• the dendrites and death of Purkinje cell bodies resulting in very few surviving Purkinje cells by 3 months
• essentially all Purkinje cells are gone at 6 months of age
• Purkinje cell dendrite attenuation in 9 weeks-old mutant mice cerebella
• by 3 months of age, the mutant cerebella are only 75% that of wild-type
• by 1 year of age, the overall cerebellar area of mutants has dropped to 50% of wild-type
• the greatest loss occurs in the molecular layer
• by 7 weeks, mutant axons show extensive torpedoes, focal swellings typical of many neuropathies

cellular
• ultrastructurally the mitochondria in mutant Purkinje cells shows dramatic defects in mitochondrial morphology, distribution, and cristae organization
• ecreased cytochrome C oxidase activity and increased succinate dehydrogenase activity in Purkinje cells of 9-weeks-old mutant mice indicating the electron transport chain dysfunction in mitochondria


Mouse Genome Informatics
cn7
    Gabra6tm2(cre)Wwis/Gabra6+
Mfn2tm1Dcc/Mfn2tm3Dcc

involves: 129 * 129S4/SvJaeSor * Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
normal phenotype
• shows no defect in balance and coordination
• no anatomical abnormality in cerebella


Mouse Genome Informatics
cn8
    Mfn2tm1Dcc/Mfn2tm3Dcc
Tg(EIIa-cre)C5379Lmgd/0

involves: 129 * 129S4/SvJaeSor * Black Swiss * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• embryos die during mid-gestation similar to Mfn2tm1Dcc homozygous embryos


Mouse Genome Informatics
cn9
    Gt(ROSA)26Sortm1.1(CAG-COX8A/Dendra2)Dcc/Gt(ROSA)26Sor+
Mfn2tm3Dcc/Mfn2tm3Dcc
Slc6a3tm1.1(cre)Bkmn/Slc6a3+

involves: 129 * 129S6/SvEvTac * C57BL/6J * SJL/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants die around 6-7 weeks of age due to malnutrition; this is most likely due to difficulty accessing food and water in normal cages due to a rearing defect
• however, when mutants are supplied with hydrated gel packs and crushed pieces of regular chow, all mutants survive beyond 6 months of age, with a majority surviving past 1 year of age

growth/size
• mutants are significantly smaller than controls by 5 weeks of age
• mutants do not gain weight after 4 weeks of age

behavior/neurological
• mutants are hunched by 5 weeks of age
• severe rearing defect as early as 4 weeks of age
• treatment of mutants with L-DOPA alleviates the motor defects
• beginning at 4-5 weeks, mutants exhibit progressive bradykinesia
• mutants exhibit a decline in the speed of movement with age compared to controls
• mutants spend twice as much time inactive at 6-7 weeks of age as controls and by 8-11 weeks of age, this increases to 6-fold increase in inactive time
• mutants are hypoactive by 5 weeks of age
• at 4-5 weeks of age, mutants travel only 68% of the distance traveled by wild-type mice and by 8-11 weeks of age, the distance traveled reduces to 34% of wild-type, indicating an age-dependent decline in locomotive activity

nervous system
• loss of dopaminergic terminals in the striatum, with a 25% reduction in dopaminergic terminals at 3 weeks of age and 76% reduction by 8-10 weeks
• mutants exhibit loss of dopaminergic efferents to the striatum, with a 25% reduction in dopaminergic terminals at 3 weeks of age and a 76% reduction by 8-10 weeks of age
• however, projections to the nucleus accumbens and olfactory tubercle are protected and the dopaminergic terminals are moderately preserved at 11-14 weeks
• dopaminergic neurons remaining have smaller cell bodies and diminished neuronal processes
• dopaminergic neurons exhibit mitochondrial fragmentation and depletion
• retrograde degeneration of substantia nigra pars compacta dopaminergic neurons and to a lesser extent in the mesolimbic pathway
• progressive, retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit, with neuronal loss first seen at 10-12 weeks, when a 52% decrease in TH-positive neurons is seen
• some degeneration is also seen in the mesolimbic pathway, although a lesser extent than in the nigrostriatal circuit
• degeneration of dopaminergic neurons occurs in a stepwise manner, with initial defects at the axon terminals, followed 1-2 months later by degeneration of the cell bodies
• mutants show decreased mitochondrial transport along nerve processes

cellular
• dopaminergic neurons exhibit mitochondrial fragmentation and depletion

skeleton

Mouse Models of Human Disease
OMIM IDRef(s)
Parkinson Disease, Late-Onset; PD 168600 J:188347


Mouse Genome Informatics
cn10
    Meox2tm1(cre)Sor/Meox2+
Mfn1tm1Dcc/Mfn1tm2Dcc
Mfn2tm3Dcc/Mfn2+

involves: 129S/SvEv * 129S4/SvJaeSor * Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• invariably die on P0


Mouse Genome Informatics
cn11
    Meox2tm1(cre)Sor/Meox2+
Mfn1tm1Dcc/Mfn1tm2Dcc
Mfn2tm1Dcc/Mfn2tm3Dcc

involves: 129S/SvEv * 129S4/SvJaeSor * Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• invariably die on P0


Mouse Genome Informatics
cn12
    Meox2tm1(cre)Sor/Meox2+
Mfn1tm2Dcc/Mfn1+
Mfn2tm1Dcc/Mfn2tm3Dcc

involves: 129S/SvEv * 129S4/SvJaeSor * Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• after birth, about one third of mutant mice die on postnatal day 1
• mutant pups are born at appropriate Mendelian ratio
• mutant mice that survive the neonatal period die by P17

behavior/neurological
• mice surviving beyond P1 cannot easily regain posture when placed on their backs
• mice surviving beyond P1 display uncoordinated limb movements, and move primarily by writhing on their abdomen

growth/size
• mice surviving beyond P1 are severely runted, likely due to feeding problems secondary to their movement disorder


Mouse Genome Informatics
cn13
    Meox2tm1(cre)Sor/Meox2+
Mfn2tm1Dcc/Mfn2tm3Dcc

involves: 129S/SvEv * 129S4/SvJaeSor * Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• mice surviving beyond P1 cannot easily regain posture when placed on their backs
• mice surviving beyond P1 display uncoordinated limb movements, and move primarily by writhing on their abdomen

growth/size
• mice surviving beyond P1 are severely runted, likely due to feeding problems secondary to their movement disorder

nervous system
• severe defect in postnatal cerebellar growth

mortality/aging
• after birth, about one third of mutant mice die on postnatal day 1
• mutant mice that survive the neonatal period die by P17
• mutant pups are born at appropriate Mendelian ratio