Induced Dimerization & Activation of FGFR in Mouse Prostate
The iDimerize Inducible Homodimerization technology is used to dissect the roles of mammalian fibroblast growth factor receptor (FGFR) sub-class members in causing prostate hyperplasia in mice. Authors show that induced FGFR1 signaling, but not FGFR2 signaling, leads to prostate hyperplasia. Paper: Freeman et al. (2003) Cancer Res. 63(23):8256–63.
Advantages of inducible dimerization
- Activate one specific FGFR
- Induce at any developmental time point
- Remove ligan to study phenotype reversibility
- Easier setup than Cre-Lox or regulated transcription systems
Mice with inducible FGFR1 and FGFR2 transgenes under the control of a prostate-specific promoter were created. Each construct encoded a membrane-targeting sequence, the tyrosine kinase domain of FGFR, and two copies of the DmrB domain, which dimerize in the presence of the B/B Homodimerizer ligand.*
After two weeks of regular injections with ligand, only mice with ectopic FGFR1 signaling developed prostate-specific hyperplasia. Receptor tyrosine phosphorylation was confirmed in both stains, suggesting phenotypic differences were due to signaling events downstream of FGFR activation.
Authors stopped ligand treatment at various time points to see if continued FGFR1 signaling is required for hyperplasia maintenance. They learned that hyperplasia is reversible prior to extensive neovascularization, providing opportunities for early intervention in prostate cancer.
Studies are presented using iDimerize components. For complete experimental details please refer to the original publication. The optimal position and copy number of fusion domains varies per study and must be determined empirically.