This strain contains a rTetR-KRAB CRISPR-generated knock-in allele inserted into the Gt(ROSA)26Sor locus. This strain also has a CRISPR-generated tetO insertion into the Tcf7l2 gene. Kr&uuml;ppel associated box domain (KRAB) is a repressive chromatin modifier domain mRNA from the murine zinc finger protein 354A (Zfp354a) gene. Tcf7l2 encodes a transcription factor that acts downstream of the canonical Wnt signaling pathway. The Wnt signaling pathway is involved in cell proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. It drives small intestine and colon tumors and is a suspected oncogene in both cancer types. Endogenous Tcf7l2 mRNA expression and splicing are unaffected in the single mutant tetO line because TREmod is inserted into intron 3 of the Tcf7l2 gene, away from the intron-exon splice sites. Feeding double mutant Rosa26-rTetR-KRAB Tcf7l2-TRE mice with doxycycline-containing food pellets rapidly and completely represses endogenous Tcf7l2 mRNA and protein expression in the small intestine within three days. Since Rosa26-rTetR-KRAB expression is ubiquitous, Tcf7l2 repression is also achieved in many other tissues including the colon, muscle and adipose tissue. This repression is reversible, both mRNA levels and protein expression return to original levels upon withdrawal of doxycycline treatment. When Tcf7l2 is continuously repressed, mice die within 10 days due to the loss of the small intestine epithelium, similar to the lethal phenotype of other germline and adult Tcf7l2 knock-out mice. To circumvent this lethality phenotype, partial Tcf7l2 repression, achieved by down-titrating the doxycycline dose, allows for long-term studies of Tcf7l2 gene function allowing the mouse to be viable for more than one year. These mice are useful for studying treatments for cachexia, a complex metabolic syndrome that causes muscle and fat loss and is often associated with cancer. Cachexia can be induced by tumor-derived factors, including growth factors, cytokines and metabolites. As it progresses into the late and severe stages, cachexia affects multiple distant organs and promotes decreased appetite, skeletal muscle atrophy, and adipolysis. Muscle atrophy can become so drastic that it may cause death by cardiac or respiratory arrest. Elevated TCF7L2 in the gastrocnemius muscle can induce atrophy by activating the transcription of multiple atrophy genes within the ubiquitin-proteasome and autophagy-lysosome systems. Repressing Tcf7l2 normalizes atrophy gene expression back to non-cachectic expression levels and restores muscle mass. This transgenic mouse is a valuable tool to study muscle atrophy across other conditions including aging, diabetes and neuromuscular disease. Additionally, TCF7L2 has been implicated in proliferation, migration, and invasion in various cancer types, such as pancreatic, gastric, and glioma. Therefore, this transgenic mouse will be useful for investigating the precise role of TCF7L2 in the progression of these cancers.

The use of this mouse model is subject to the terms and conditions of the Limited Use Label License from Caribou Biosciences, Inc.

The use of this mouse strain or other product (the "Licensed Product") is subject to the terms and conditions of the Limited License from The Broad Institute.

This strain contains a rTetR-KRAB knock-in allele inserted into the Gt(ROSA)26Sor locus and also has a tetO inserted into the Tcf7l2 gene. With these mice, down-titrating doxycycline doses allows for long-term studies of Tcf7l2 gene function by increasing mouse viability to more than one year. This mouse strain is a valuable tool to study muscle atrophy and cachexia across other conditions including aging, diabetes, cancer, and neuromuscular disease. Additionally, TCF7L2 has been implicated in proliferation, migration, and invasion in various cancer types, such as pancreatic, gastric, and glioma. Therefore, this transgenic mouse will be useful for investigating the precise role of TCF7L2 in the progression of these cancers.

Typically mice are recovered in 12-16 weeks. Contact Customer Service to place an order or for more information.

<a target="_blank" href="https://www.jax.org/jax-mice-and-services/customer-support" rel="noreferrer">Contact Customer Service</a> for more information.