Phenotypes associated with this allele
Allelic
Composition |
Tsc1tm1.1Djk/Tsc1tm1.1Djk
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Genetic
Background |
either: 129S4/SvJae-Tsc1tm1Djk or (involves: 129S4/SvJae * BALB/cJ) or (involves: 129S4/SvJae * C57BL/6J) |
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| Find Mice |
Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tsc1tm1.1Djk mutation
(1 available);
any
Tsc1 mutation
(69 available)
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mortality/aging
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• viability of embryos steadily declined from E9 to E13.5
• no viable null embryos were observed beyond E13.5
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embryo
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• typically by approximately one embryonic day less developed
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liver/biliary system
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• hypoplastic liver with poorly developed other abdominal organs
• the liver and other abdominal organs had dilated vascular channels
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homeostasis/metabolism
cardiovascular system
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• sightly enlarged heart that was shifted inferiorly
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• viable E9-12.5 embryo often had pericardial effusions
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growth/size/body
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• sightly enlarged heart that was shifted inferiorly
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• typically by approximately one embryonic day less developed
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integument
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• viable E9-12.5 embryos are paler
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Allelic
Composition |
Tsc1tm1.1Djk/Tsc1+
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Genetic
Background |
either: 129S4/SvJae-Tsc1tm1Djk or (involves: 129S4/SvJae * BALB/cJ) or (involves: 129S4/SvJae * C57BL/6J) |
|
| Find Mice |
Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tsc1tm1.1Djk mutation
(1 available);
any
Tsc1 mutation
(69 available)
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mortality/aging
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• increased premature death before 18 month of age for female and in a co-isogenic 129SvJae background, due to increased incidence of severe liver hemangioma leading to spontaneous bleeding
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neoplasm
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• consisting of aberrant vascular channels of highly variable size that often had cuboidal-columnar endothelial cells, and proliferation of smooth muscle cells
• these lesions were seen in 67% males and 93% females
• these lesions are more severe in female compared to male, causing more death in female
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• multiple bilateral renal cystadenomas in all heterozygous mice by 15-18 months of age
• varied from pure cysts with cuboidal lining cells to cysts with papillary projections, to a solid adenomas
• Background Sensitivity: there were more cystadenomas in BALB/cJ hybrid background, but no sex difference were seen
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• 6 out of 31 heterozygous mice showed histologic features consistent with progression to renal cell carcinoma
• no evidence of metastasis was found in those mice
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• 1out of 31 heterozygous mice showed hemangiosarcoma of the forepaw
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renal/urinary system
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• multiple bilateral renal cystadenomas in all heterozygous mice by 15-18 months of age
• varied from pure cysts with cuboidal lining cells to cysts with papillary projections, to a solid adenomas
• Background Sensitivity: there were more cystadenomas in BALB/cJ hybrid background, but no sex difference were seen
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• 6 out of 31 heterozygous mice showed histologic features consistent with progression to renal cell carcinoma
• no evidence of metastasis was found in those mice
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liver/biliary system
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• consisting of aberrant vascular channels of highly variable size that often had cuboidal-columnar endothelial cells, and proliferation of smooth muscle cells
• these lesions were seen in 67% males and 93% females
• these lesions are more severe in female compared to male, causing more death in female
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mortality/aging
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• median survival of 35 days, with no survivors beyond 65 days
(J:121858)
• mice treated with rapamycin or RAD001 (mTOR inhibitor) show 90-100% survival to 80 days of age compared to median survival of 33 days for untreated mutants
(J:136366)
• discontinuation of drug treatment at P30 results in clinical symptom improvement for 1-2 weeks followed by clinical deterioration and death at 79 days for rapamycin-treated and 77 days for RAD001-treated mutants
(J:136366)
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growth/size/body
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• after P5 until death, mutants fail to gain weight at same rate as controls; average maximum weight is 10 grams
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nervous system
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• mice develop clinical seizures, spontaneous and some provoked in most part by physical simulation; both types of seizures are mild or severe
• severe seizures are characterized by brief behavioral arrest, followed by several seconds of clonic activity, followed by tonic extensor posturing of trunk and limbs for 15-45 seconds
• after P21, suspension by the tail results in gentle spinning leading severe seizure activity, followed by bradycardia and death
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• only mild seizures occur spontaneously, characterized by brief myoclonic jerking of head and torso
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• enlarged cells are seen outside cerebral cortex, in other parts of brain including thalamus, hypothalamus and brainstem
• no increased cell loss or degeneration is observed in regions containing anomalous enlarged cells
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• brain weight to body weight ratio is significantly greater (2.4-fold) in mutants compared to wild-type; with rapamycin/RAD001 treatment, difference from control is significantly reduced but still observed
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• enlarged cells are observed in hilus
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• enlarged cells are seen throughout pyramidal cell layer, particularly in CA3 region
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• enlarged ectopic cells are seen outside the CA1-CA3 fields in stratum oriens and stratum radiatum
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• laminar organization is less distinct than in the 6 cortical layers of controls
(J:121858)
• unusually large cells are observed in all six layers in mutants, particularly in layer V; layer of enlarged cells is seen at gray-white matter border throughout cerebral cortex at P21
(J:121858)
• mutants display subset of enlarged pS6-positive cells at base of cortex and in cortical layer V; drug treatment results in marked reduction in size of enlarged cells
(J:136366)
• mild cortical disorganization is observed in mutants with or without rapamycin treatment
(J:136366)
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• contains some enlarged cells
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• Nissl bodies and filamentous aggregates are often detected in enlarged neurons, prominently in brainstem but rarely in enlarged cortical cells
(J:121858)
• some neurons are aberrantly localized outside primary pyramidal cell layers; ectopic neurons are isolated, not organized into clusters or columns
(J:121858)
• some neurons in somatosensory cortex show 60% increase in soma size relative to controls
(J:121858)
• many pyramidal neurons demonstrate dysplastic features including increased size and thicker dendritic arbors compared to control neurons
(J:121858)
• population of neurons in lateral somatosensory cortex are considerably enlarged compared with those in controls; size is significantly reduced after drug treatment (from 1.8-fold to 1.2-fold), but effect reverses when treatment is stopped
(J:136366)
• in somatosensory cortex, layer V neurons often have major dendrites extending tangentially and diagonally to the pia, in contrast to control neurons which mainly have long apical dendrite oriented directly toward pial surface; rapamycin treatment initiated at P7 does not significantly decrease abnormally oriented dendrite percentage
(J:136366)
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• in mutant brains, neurons appear to be still actively growing after P14-21, whereas wild-type neurons have stopped growing
• this may result in the hypomyelination, due to secondary myelination failure
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• in hippocampal neuron cultures, neuronal dendritic spine density is reduced >20% compared to controls
• with rapamycin treatment, spine density is marginally increased; spine length however is increased 9% compared to treated and untreated controls or untreated mutants
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• hypomyelination is observed in brains of mutants
(J:121858)
• oligodendrocyte number and distribution appears similar to wild-type
(J:121858)
• myelination particularly in cortex is impaired due to decreased myelin production by oligodendrocytes; rapamycin treatment works to restore myelination throughout brain with greatest improvement in cortex and hippocampus
(J:136366)
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• mice aged P21-48 display 3 types of electrographic abnormalities: short spike bursts observed in all mice examined, occasionally spontaneous period of desynchronization with electrodecrement and at low incidence, frequent high-amplitude sharp waves
• interictal (seizure) 1-2 second bursts of high-amplitude 7-8 hertz spikes are observed with high frequency compared with controls; these are without obvious clinical correlate
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behavior/neurological
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• clasping behavior and tremor are significantly ameliorated by rapamycin/RAD001 treatment relative to untreated animals at 30, 60, and 100 days postnatal
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• display posterior limb-clasping behavior when lifted by tail
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• progressive high-frequency trunk and limb tremor apparent by P10
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• at death, usually in third to fifth postnatal week, mice are found with extensor posture of fore- and hindlimbs
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• develops by by third or fourth postnatal week
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• tail dorsiflexion is exhibited
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• mice show progressive decline in activity with limited mobility by third or fourth postnatal week
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• mice develop clinical seizures, spontaneous and some provoked in most part by physical simulation; both types of seizures are mild or severe
• severe seizures are characterized by brief behavioral arrest, followed by several seconds of clonic activity, followed by tonic extensor posturing of trunk and limbs for 15-45 seconds
• after P21, suspension by the tail results in gentle spinning leading severe seizure activity, followed by bradycardia and death
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• only mild seizures occur spontaneously, characterized by brief myoclonic jerking of head and torso
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skeleton
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• kyphosis is significantly improved in rapamycin/RAD001-treated mice compared with untreated mutants
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cellular
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• in mutant brains, neurons appear to be still actively growing after P14-21, whereas wild-type neurons have stopped growing
• this may result in the hypomyelination, due to secondary myelination failure
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mortality/aging
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• as in Lin28atm1.1Gqda homozygotes
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growth/size/body
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• dwarfism as in Lin28atm1.1Gqda homozygotes
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growth/size/body
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N |
• male mice exhibit normal growth
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Analysis Tools