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Strain Name:

STOCK Tsc1tm1Djk/J

Stock Number:

005680

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Genes & Alleles   Tsc1;   Tsc1tm1Djk;

Product Information

Strain Details

Type JAX® GEMM® Strain - Mutant Stock
Additional information on JAX® GEMM® Strains.
Type JAX® GEMM® Strain - Targeted Mutation
Mating SystemHomozygote x Homozygote         (Female x Male)
Specieslaboratory mouse
Donating Investigator David Kwiatkowski,   Brigham and Women's Hospital
Generation?+N1F5 (24-JUL-07)

Strain Description
Homozygous mice are viable, fertile, normal in size, have normal expression of hamartin (the targeted gene's protein product), have no growth or behavioral defects, and are devoid of tumors through age 18 months. This mutant carries a "floxed" allele of the endogenous gene. When combined with a mutant carrying a Cre recombinase gene under the control of a promoter of interest, exons 17 and 18 of Tsc1 are deleted in the tissue of interest. This mutant may be useful in many tissue-specific studies including tuberous sclerosis or other hamartoma syndromes, regulation of the actin cytoskeleton and motility, cellular and organismal glucose homeostasis, cell growth responses, apoptosis regulation, and regulation of cell size.

When bred to a strain expressing Cre recombinase in neuronal cells (see Stock No. 003966 for example), this mutant mouse strain may be useful in studies of tuberous sclerosis.

Importation of this model was supported by the Tuberous Sclerosis Alliance.

Strain Development
A targeting vector containing a loxP-flanked neomycin resistance-thymidine kinase gene cassette preceding exon 17 and a third loxP site downstream of exon 18 was electroporated into 129S4/SvJae derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. Chimeric mice were backcrossed for germ-line transmission to C57BL/6J, BALB/cJ, or 129/SvJae mice. The resulting heterozygotes were intercrossed to produce homozygotes on a mixed background.

Related Disease (OMIM) Terms

Tuberous Sclerosis; TS
Mammalian Phenotype Terms assigned by genotype

The following phenotype relates to a compound genotype created using this strain.
Contact JAX® Services jaxservices@jax.org for customized breeding options.

Tsc1tm1Djk/Tsc1tm1.1Djk Tg(Syn1-cre)671Jxm/0

        involves: 129S4/SvJae * C57BL/6 * CBA   (conditional)
  • life span-post-weaning/aging
  • premature death (MGI Ref ID J:136366)
    • 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
    • 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
    • median survival of 35 days, with no survivors beyond 65 days
  • growth/size phenotype
  • postnatal slow weight gain (MGI Ref ID J:121858)
    • after P5 until death, mutants fail to gain weight at same rate as controls; average maximum weight is 10 grams
  • nervous system phenotype
  • abnormal brain morphology (MGI Ref ID J:121858)
    • 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
    • abnormal cerebral cortex morphology (MGI Ref ID J:136366)
      • 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
      • mild cortical disorganization is observed in mutants with or without rapamycin treatment
      • laminar organization is less distinct than in the 6 cortical layers of controls
      • 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
      • abnormal neocortex morphology (MGI Ref ID J:121858)
        • contains some enlarged cells
      • abnormal pyramidal neuron morphology (MGI Ref ID J:121858)
        • many pyramidal neurons demonstrate dysplastic features including increased size and thicker dendritic arbors compared to control neurons
    • abnormal dentate gyrus morphology (MGI Ref ID J:121858)
      • enlarged cells are observed in hilus
    • abnormal hippocampus pyramidal cell layer (MGI Ref ID J:121858)
      • enlarged cells are seen throughout pyramidal cell layer, particularly in CA3 region
    • abnormal hippocampus region morphology (MGI Ref ID J:121858)
      • enlarged ectopic cells are seen outside the CA1-CA3 fields in stratum oriens and stratum radiatum
    • increased brain weight (MGI Ref ID J:136366)
      • 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
  • abnormal brain wave pattern (MGI Ref ID J:121858)
    • 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
  • abnormal myelination (MGI Ref ID J:136366)
    • 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
    • hypomyelination is observed in brains of mutants
    • oligodendrocyte number and distribution appears similar to wild-type
  • abnormal neurogenesis (MGI Ref ID J:121858)
    • 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
  • abnormal neuron morphology (MGI Ref ID J:136366)
    • 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
    • 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
    • Nissl bodies and filamentous aggregates are often detected in enlarged neurons, prominently in brainstem but rarely in enlarged cortical cells
    • some neurons are aberrantly localized outside primary pyramidal cell layers; ectopic neurons are isolated, not organized into clusters or columns
    • some neurons in somatosensory cortex show 60% increase in soma size relative to controls
    • abnormal dendrite morphology (MGI Ref ID J:136366)
      • 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
  • seizures (MGI Ref ID J:121858)
    • 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
    • sporadic seizures (MGI Ref ID J:121858)
      • only mild seizures occur spontaneously, characterized by brief myoclonic jerking of head and torso
  • behavior/neurological phenotype
  • abnormal involuntary movement (MGI Ref ID J:136366)
    • clasping behavior and tremor are significantly ameliorated by rapamycin/RAD001 treatment relative to untreated animals at 30, 60, and 100 days postnatal
    • increased startle reflex (MGI Ref ID J:121858)
      • apparent by P10
    • limb grasping (MGI Ref ID J:121858)
      • display posterior limb-clasping behavior when lifted by tail
    • tremors (MGI Ref ID J:121858)
      • progressive high-frequency trunk and limb tremor apparent by P10
  • abnormal limb posture (MGI Ref ID J:121858)
    • at death, usually in third to fifth postnatal week, mice are found with extensor posture of fore- and hindlimbs
  • hunched posture (MGI Ref ID J:121858)
    • develops by by third or fourth postnatal week
  • hyperactivity (MGI Ref ID J:121858)
    • apparent by P10
  • hypoactivity (MGI Ref ID J:121858)
    • mice show progressive decline in activity with limited mobility by third or fourth postnatal week
  • seizures (MGI Ref ID J:121858)
    • 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
    • sporadic seizures (MGI Ref ID J:121858)
      • only mild seizures occur spontaneously, characterized by brief myoclonic jerking of head and torso
  • straub tail (MGI Ref ID J:121858)
    • tail dorsiflexion is exhibited
  • skeleton phenotype
  • abnormal spine curvature (MGI Ref ID J:136366)
    • kyphosis is significantly improved in rapamycin/RAD001-treated mice compared with untreated mutants
  • hearing/vestibular/ear phenotype
  • increased startle reflex (MGI Ref ID J:121858)
    • apparent by P10

Tsc1tm1Djk/Tsc1tm1Djk Tg(Syn1-cre)671Jxm/0

        involves: 129S4/SvJae * C57BL/6 * CBA   (conditional)
  • life span-post-weaning/aging
  • premature death (MGI Ref ID J:121858)
  • growth/size phenotype
  • abnormal body size (MGI Ref ID J:121858)
  • nervous system phenotype
  • abnormal nervous system morphology (MGI Ref ID J:121858)
  • abnormal nervous system physiology (MGI Ref ID J:121858)
  • behavior/neurological phenotype
  • abnormal behavior (MGI Ref ID J:121858)

Gene & Allele Details

Allele Symbol Tsc1tm1Djk
Allele Name targeted mutation 1, David J Kwiatkowski
Common Name(s) Tsc1c;
Mutation Made By David Kwiatkowski,   Brigham and Women's Hospital
Strain of Origin129S4/SvJae
ES Cell Line NameJ1
ES Cell Line Strain129S4/SvJae
Gene Symbol and Name Tsc1, tuberous sclerosis 1
Chromosome 2
Gene Common Name(s) KIAA0243; LAM; MGC86987; TSC; hamartin;
Molecular Note A floxed neo-TK cassette was inserted into the intron preceding exon 17 and a third loxP site was introduced downstream of exon 18 by homologous recombination. [MGI Ref ID J:75243]

Control Information

  Control
   None Available
 
  Considerations for Choosing Controls

Genotyping Protocols

Tsc1tm1Djk

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, these mice are maintained as homozygotes.
Diet Information LabDiet® 5K52/5K67

Additional Web Information

Cre-lox or FLP-FRT Systems
Genetic Quality Control Annual Report

Animal Health Reports

Room Number           AX11

Research Applications

This mouse can be used to support research in many areas including:

Research Tools
Cancer Research (Hamartoma Syndromes)
Cre-lox System (loxP-flanked Sequences)

References

Selected Reference(s)

Kwiatkowski DJ; Zhang H; Bandura JL; Heiberger KM; Glogauer M; el-Hashemite N; Onda H. 2002. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet 11(5):525-34. [PubMed: 11875047]  [MGI Ref ID J:75243]

Additional References

Price and Supply Information

Strain Name: STOCK Tsc1tm1Djk/J
Stock Number: 005680

Price Details

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Supply Details

Standard SupplyRepository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.
Supply Notes Usually shipped between four and eight weeks of age.
This strain is included in the Induced Mutant Resource Colony collection.
Genomic DNA is available for this strain from the Mouse DNA Resource.
LicensingSee General Terms and Conditions below for Licensing and Use Restrictions  
Control InformationView Control Information in Strain Details.

General Terms and Conditions

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Effective September 26, 2007: License Requirements for Strains using Cre-lox Technology only apply in Canada, see Licenses for Strains using Cre-lox Technology.

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.
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