Tsc2+/- mice are useful in studying Tuberous sclerosis. In addition, the mTOR hyperactivation exhibited by Tsc2+/- mice causes impaired basal neuronal autophagy, resulting in autism spectrum disorder (ASD)-like basal dendritic spine pathology and social recognition/interaction deficits.
David J. Kwiatkowski, Brigham and Women's Hospital
Exon 2 of the tuberous sclerosis 2 gene (Tsc2) has been replaced by a neo cassette, abolishing gene expression. TSC2 is a putative tumor supressor. Mutation of TSC2 have been associated with the onset of tuberous sclerosis complex (TSC) which is characterized by the formation of non-malignant tumors in many different organs. Heterozygous (Tsc2+/-) mice are viable and fertile. Homozygous (Tsc2-/-) mice have an embryonic lethal phenotype, failing to develop past embryonic days 9.5 to 12.5 due to hepatic hypoplasia. Cultured neuroepithelial progenitor cells isolated from embryonic day 10.5 embryos display abnormal growth and differentiation. All heterozygotes develop multiple bilateral renal cystadenomas by 12-15 months of age. By 15 months, about half develop liver hemangiomas (more common in females than in males). Less than 10% develop extremity angiosarcomas or renal carcinoma. Little or no gene product (protein) is detected by Western blot in renal cystadenomas. PCR analysis reveals loss of the wildtype allele in about 30% of lesions. Phenotype variability is dependent on genetic background.
Tsc2 haploinsufficiency causes mTOR hyperactivation: the subsequent autophagy inhibition results in autism spectrum disorder (ASD)-like basal dendritic spine pathology and social recognition/interaction deficits. Rapamycin treatment rescues the dendritic spine pruning defect and social abnormalities. Tsc2+/- mice do not exhibit stereotyped/repetitive behavior, motor defects or anxiety-like behavior.
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exon 2 of the tuberous sclerosis 2 locus on chromosome 17. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to C57BL/6 mice. Heterozygotes were then intercrossed.
|Allele Name||targeted mutation 1, David J Kwiatkowski|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||Tsc2-; Tsc-|
|Gene Symbol and Name||Tsc2, tuberous sclerosis 2|
|Gene Synonym(s)||LAM; Nafld; PPP1R160; Rc; TSC4; tuberin|
|Strain of Origin||129S4/SvJae|
|Molecular Note||A neomycin cassette was inserted into the second coding exon of the gene.|
|Mutations Made By|| |
David Kwiatkowski, Brigham and Women's Hospital
When maintaining a live colony, heterozygous mice may be bred together or to wildtype mice from the colony. Homozygotes have an embryonic lethal phenotype. The expected coat color is Black.
When using the B6;129S4-Tsc2tm1Djk/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #004686 in your Materials and Methods section.
|Heterozygous or wildtype for Tsc2<tm1Djk>|
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