The forkhead box (FOX) family of transcription factors are expressed during development and are associated with a number of cellular and developmental differentiation processes. The forkhead box C2 gene encodes FOXC2 (or MFH1) which is required during early development of the kidneys (podocyte differentiation and glomerular basement membrane maturation). In addition, FOXC2 facilitates collecting lymphatic vessel maturation (and the formation of lymphatic/lymphovenous valves therein). FOXC2 is also involved in early development of the heart.

The Foxc2CreERT2 knock-in/knock-out allele has a tamoxifen-inducible Cre recombinase gene (CreERT2) replacing the Foxc2 translational start site - this abolishes endogenous gene function and results in the Foxc2 promoter/enhancer regions directing cre/ERT2 expression. CreERT2 fusion gene activity is inducible; observed following tamoxifen administration. When Foxc2CreERT2 mice are bred with mice containing lox-flanked (floxed) sequences, tamoxifen-inducible Cre-mediated recombination will result in deletion of floxed sequences in Foxc2-expressing cells in the offspring.

 Specifically, CreERT2 expression recapitulates the endogenous Foxc2 expression pattern. The donating investigator summarizes that Foxc2CreERT2 mice have tamoxifen-inducible Cre recombinase activity in lymphovenous valves, mural cells and bones of the developing embryo. They have not examined CreERT2 expression in other tissues. The donating investigator reports there is no Cre recombinase activity prior to tamoxifen exposure. 

No functional FOXC2 protein is generated by the Foxc2CreERT2 allele (immunohostochemistry using Foxc2 antibody). Mice homozygous for the Foxc2CreERT2 allele (on a C57BL/6 background) die ~E12.5-E16.5. Mice heterozygous for the Foxc2CreERT2 allele (on a C57BL/6 background) exhibit a variable phenotype. By E14.5, ~50% of heterozygous embryos develop severe edema with no identifiable lymphovenous valves (LVVs) or LVV-forming endothelial cells (LVV-ECs). The remaining heterozygous embryos were grossly normal with identifiable LVV-ECs or LVVs - however they contain only one LVV (compared to two in the LVV-complex of wildtype control embryos). The donating investigator reports a small percentage of heterozygotes die in the first week after birth, but heterozygous mice alive at postnatal day seven will survive to adulthood with normal breeding characteristics and lifespan. They also observe 100% incidence of distichiasis (two rows of eye lashes) in heterozygous animals.

The Cre-ERT2 fusion protein consists of Cre recombinase fused to a triple mutant form of the human estrogen receptor which does not bind its natural ligand (17&beta;-estradiol) at physiological concentrations but will bind the synthetic estrogen receptor ligands 4-hydroxytamoxifen (OHT or tamoxifen) and, with lesser sensitivity, ICI 182780. Restricted to the cytoplasm, Cre-ERT2 can only gain access to the nuclear compartment after exposure to tamoxifen. To counteract the mixed estrogen agonist effects of tamoxifen injections, which can result in late fetal abortions in pregnant mice, progesterone may be coadministered.

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The Foxc2CreERT2 knock-in/knock-out allele was designed to both abolish endogenous gene function and allow the Foxc2 promoter/enhancer regions to direct tamoxifen-inducible Cre recombinase expression to lymphovenous valves, mural cells and bones of the developing embryo. These mice may be useful for tamoxifen-inducible recombination of lox-flanked (floxed) alleles in developmental studies (including kidney, lymphatic vessels, lymphovenous valves and heart).

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