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Allele Symbol Allele Name Allele ID |
Mfn2tm3Dcc targeted mutation 3, David C Chan MGI:3779081 |
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| Summary |
15 genotypes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• fibroblast derived from mutant animals exhibit Cre-dependent mitochondrial fragmentation
• loss of mtDNA nucleoids from a significant fraction of mitochondria
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• a progressive decline in coordination and balance in rotarod test
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• at 2 months of age, they begin to exhibit a slightly shaky gait
• mutants are indistinguishable from wild-type littermates first 2 mo
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• ultrastructurally the mitochondria in mutant Purkinje cells shows dramatic defects in mitochondrial morphology, distribution, and cristae organization
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• obvious neuro-degeneration of cerebella over time
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• 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
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• Purkinje cell dendrite attenuation in 9 weeks-old mutant mice cerebella
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• 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
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• by 7 weeks, mutant axons show extensive torpedoes, focal swellings typical of many neuropathies
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• ultrastructurally the mitochondria in mutant Purkinje cells shows dramatic defects in mitochondrial morphology, distribution, and cristae organization
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• 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
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• normal cerebella containing a uniform, unbroken Purkinje cell monolayer similar to that in wild-type mice at 9-week-old
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• Purkinje cell death in 9 weeks-old mutant mice cerebella
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• Purkinje cell dendrite attenuation in 9 weeks-old mutant mice cerebella
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• 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
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• 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
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• mice surviving beyond P1 cannot easily regain posture when placed on their backs
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• mice surviving beyond P1 display uncoordinated limb movements, and move primarily by writhing on their abdomen
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• mice surviving beyond P1 are severely runted, likely due to feeding problems secondary to their movement disorder
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• severe defect in postnatal cerebellar growth
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• 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
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• mice surviving beyond P1 cannot easily regain posture when placed on their backs
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• mice surviving beyond P1 display uncoordinated limb movements, and move primarily by writhing on their abdomen
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• mice surviving beyond P1 are severely runted, likely due to feeding problems secondary to their movement disorder
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• mitochondria in mutant Purkinje cells in mixed cerebellar cultures tend to cluster together in the cell body and do not enter the dendritic tracts
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• markedly higher levels of apoptosis in mutant cerebella as early as p6 and continuing through the second postnatal week
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• 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
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• reduced growth and deterioration of Purkinje cell dendrite during the second postnatal week
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• 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
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• mitochondria in mutant Purkinje cells in mixed cerebellar cultures tend to cluster together in the cell body and do not enter the dendritic tracts
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• markedly higher levels of apoptosis in mutant cerebella as early as p6 and continuing through the second postnatal week
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• shows no defect in balance and coordination
• no anatomical abnormality in cerebella
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• embryos die during mid-gestation similar to Mfn2tm1Dcc homozygous embryos
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• 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
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• mutants are significantly smaller than controls by 5 weeks of age
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• mutants do not gain weight after 4 weeks of age
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• mutants are hunched by 5 weeks of age
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• severe rearing defect as early as 4 weeks of age
• treatment of mutants with L-DOPA alleviates the motor defects
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• 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
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• 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
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• 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
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• 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
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• dopaminergic neurons remaining have smaller cell bodies and diminished neuronal processes
• dopaminergic neurons exhibit mitochondrial fragmentation and depletion
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• retrograde degeneration of substantia nigra pars compacta dopaminergic neurons and to a lesser extent in the mesolimbic pathway
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• 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
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• mutants show decreased mitochondrial transport along nerve processes
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• dopaminergic neurons exhibit mitochondrial fragmentation and depletion
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Parkinson's disease | DOID:14330 |
OMIM:PS168600 |
J:188347 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• at P42, late-stage spermatocytes and round spermatids appear to gradually vacuolize
• TEM analysis of adult testes showed mitochondrial swelling and fragmentation in male germ cells
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• at P42, late-stage spermatocytes and round spermatids are decreased in number
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• adult males show a dramatic reduction in the number of spermatozoa retrieved from the cauda epididymis
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• TUNEL assays show a significantly increased number of apoptotic cells in the testes at P35 and P56
• however, testis histology is normal at P7-P28 and no increase in apoptosis is noted at P14 and P28
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• male germ cells exhibit increased mitochondrial fission
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• from P35, most male germ cells are gradually lost by apoptosis
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• as adult males age, the number of severely atrophic seminiferous tubules is increased
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• as adult males age, seminiferous tubules become severely atrophic and vacuolated (P60 to P120)
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• testes are significantly smaller at P56
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• testis weight/body weight ratio is significantly decreased from P35 to P120
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• males show age-dependent spermatogenic defects, with germ cells starting to decline after P35
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• only ~2% of epididymal sperm display normal morphology versus ~80% in wild-type controls
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• ~14% of sperm exhibit a coiled tail
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• ~31% of sperm exhibit a bent head
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• ~53% of sperm are acephalic
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• at P42, round spermatids are decreased in number and appear to gradually vacuolize
• analysis of the mitochondrial aspect ratio (AR) distribution (where AR is ratio of the major axis to the minor axis of mitochondria) showed an increased % of short mitochondria in round spermatids
• the distance between mitochondria and endoplasmic reticulum (ER) is increased by ~16% while the % of mitochondria-ER contacts is reduced by almost 50% and the ER-mitochondria contact coefficient (ERMICC) is reduced by >30% in round spermatids
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• at P42, late-stage spermatocytes are decreased in number and appear to gradually vacuolize
• at P60, pachytene spermatocytes show a significantly increased thickness of the inter-mitochondrial cement (IMC)
• at P18, immunostaining of calreticulin -- a mitochondria-associated ER membranes (MAMs) and ER marker protein -- showed a diffused granular pattern in the cytoplasm of spermatocytes instead of the continuous perinuclear localization seen in controls; at P60, calreticulin signals appear to be reduced and show diffused granular distribution
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• epididymis is significantly smaller at P56
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• all males fail to produce offspring after mating with fertility-proven adult wild-type females for 5 months
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N |
• immunofluorescent images of ATP5A (an outer mitochondria membrane marker) showed normal mitochondrial distribution in testicular sections at P25
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• at P42, late-stage spermatocytes and round spermatids appear to gradually vacuolize
• TEM analysis of adult testes showed mitochondrial swelling and fragmentation in male germ cells
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• only ~2% of epididymal sperm display normal morphology versus ~80% in wild-type controls
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• ~14% of sperm exhibit a coiled tail
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• ~31% of sperm exhibit a bent head
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• ~53% of sperm are acephalic
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• at P42, round spermatids are decreased in number and appear to gradually vacuolize
• analysis of the mitochondrial aspect ratio (AR) distribution (where AR is ratio of the major axis to the minor axis of mitochondria) showed an increased % of short mitochondria in round spermatids
• the distance between mitochondria and endoplasmic reticulum (ER) is increased by ~16% while the % of mitochondria-ER contacts is reduced by almost 50% and the ER-mitochondria contact coefficient (ERMICC) is reduced by >30% in round spermatids
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• at P42, late-stage spermatocytes are decreased in number and appear to gradually vacuolize
• at P60, pachytene spermatocytes show a significantly increased thickness of the inter-mitochondrial cement (IMC)
• at P18, immunostaining of calreticulin -- a mitochondria-associated ER membranes (MAMs) and ER marker protein -- showed a diffused granular pattern in the cytoplasm of spermatocytes instead of the continuous perinuclear localization seen in controls; at P60, calreticulin signals appear to be reduced and show diffused granular distribution
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• at P42, late-stage spermatocytes and round spermatids are decreased in number
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• adult males show a dramatic reduction in the number of spermatozoa retrieved from the cauda epididymis
|
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• at P60, round spermatids exhibit a fragmented ER structure instead of the tube-like cisternae structures seen in control spermatids
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• TEM analysis of adult testes showed mitochondrial swelling and fragmentation in male germ cells
• at P60, pachytene spermatocytes show a significantly increased thickness of the inter-mitochondrial cement (IMC)
• analysis of the mitochondrial aspect ratio (AR) distribution (where AR is ratio of the major axis to the minor axis of mitochondria) showed an increased % of short mitochondria in round spermatids
• the distance between mitochondria and endoplasmic reticulum (ER) is increased by ~16% while mitochondria-ER contacts are reduced by almost 50% and the ER-mitochondria contact coefficient (ERMICC) is reduced by >30% in round spermatids
• at P18, immunostaining of calreticulin -- a mitochondria-associated ER membranes (MAMs) and ER marker protein -- showed a diffused granular pattern in the cytoplasm of spermatocytes instead of the continuous perinuclear localization seen in controls; at P60, calreticulin signals appear to be reduced and show diffused granular distribution
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• adult testes show a significant increase in mitochondrial DNA copy number at P60
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• TUNEL assays show a significantly increased number of apoptotic cells in the testes at P35 and P56
• however, testis histology is normal at P7-P28 and no increase in apoptosis is noted at P14 and P28
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• cytochrome c oxidase (COX, complex IV) activity is increased in adult testis sections
• in contrast, succinate dehydrogenase (SDH, complex II) activity is normal
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• male germ cells exhibit increased mitochondrial fission
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• from P35, most male germ cells are gradually lost by apoptosis
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• male germ cells exhibit increased mitochondrial fission
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• TUNEL assays show a significantly increased number of apoptotic cells in the testes at P35 and P56
• however, testis histology is normal at P7-P28 and no increase in apoptosis is noted at P14 and P28
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• as adult males age, the number of severely atrophic seminiferous tubules is increased
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• as adult males age, seminiferous tubules become severely atrophic and vacuolated (P60 to P120)
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• testes are significantly smaller at P56
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• testis weight/body weight ratio is significantly decreased from P35 to P120
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• almost no round spermatids are detected in testes at P25
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• diameter of seminiferous tubules is significantly decreased at P14, P18, P25 and P60
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• adult testes show a significantly higher number of atrophic and vacuolated seminiferous tubules
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• adult testis size is much smaller than that in either single conditional knockout
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• adult testis weight/body weight ratio is significantly lower than that in either single conditional knockout
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• at P25 and P56, double conditional mutant males exhibit much more severe spermatogenic defects than either single conditional knockout
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• almost no round spermatids are detected in testes at P25
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• at P25, mitochondria are abnormally aggregated to one side of the cytoplasm in spermatocytes, unlike in either single conditional knockout where mitochondria distribution is normal
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• males fail to complete meiosis; almost no post-meiotic round spermatids are found at P25
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• adult epididymis size is much smaller than that in either single conditional knockout
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• almost no round spermatids are detected in testes at P25
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• at P25, mitochondria are abnormally aggregated to one side of the cytoplasm in spermatocytes, unlike in either single conditional knockout where mitochondria distribution is normal
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• almost no round spermatids are detected in testes at P25
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• at P25, mitochondria are abnormally aggregated to one side of the cytoplasm in spermatocytes, unlike in either single conditional knockout where mitochondria distribution is normal
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• males fail to complete meiosis; almost no post-meiotic round spermatids are found at P25
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• diameter of seminiferous tubules is significantly decreased at P14, P18, P25 and P60
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• adult testes show a significantly higher number of atrophic and vacuolated seminiferous tubules
|
|
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• adult testis size is much smaller than that in either single conditional knockout
|
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• adult testis weight/body weight ratio is significantly lower than that in either single conditional knockout
|
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|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 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
|
|
• 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
|
|
• mice surviving beyond P1 are severely runted, likely due to feeding problems secondary to their movement disorder
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 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
|
|
• mice surviving beyond P1 are severely runted, likely due to feeding problems secondary to their movement disorder
|
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• severe defect in postnatal cerebellar growth
|
|
• after birth, about one third of mutant mice die on postnatal day 1
|
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• mutant mice that survive the neonatal period die by P17
• mutant pups are born at appropriate Mendelian ratio
|
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 05/07/2024 MGI 6.23 |
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