Figure 1.

Floxed alleles of genes with a specific function in TH signaling and their Cre-mediated recombination products. Cre recombination deletes the Dio2^lox from the exon encoding the catalytic domain of type 2 deiodinase (90). Elimination of Dio2 prevents the local deiodination of T₄ and produces a local T₃ deficiency, in several tissues, including several brain areas, skeletal muscle, skin, pituitary, inner ear, and adipose tissues. The TRα^AMI allele (84) carries a floxed cassette with polyadenylation signal, preventing expression of a downstream cDNA encoding the TRα1^L400R dominant-negative mutant receptor receptor (mutation is indicated by the star). Cre-mediated recombination eliminates the cassette and triggers TRα1^L400R expression in virtually any cell type because Thra expression is nearly ubiquitous. The IRES-TauLacZ cassette was introduced to monitor recombination by testing for β-galactosidase activity, which is, however, too low for easy detection. Therefore, assessment of recombination usually relies on the presence of a supplementary reporter transgene (122, 123). Because a strong phenotype is observed in heterozygous mice, new Cre/TRα^AMI combinations can be generated within a single mouse generation. TRβ^lox (101) allows the elimination of exon 4 encoding the DNA-binding domain (DBD) shared by TRβ1 and TRβ2 and introduction of a frameshift for translational arrest. P1 and P2 are transcription promoters for TRβ1 and TRβ2 mRNA transcription. It can be used to eliminate TRβ1/2-mediated response in cells that express this receptor: hepatocytes, cardiomyocytes, pituitary thyrotropes, retina photoreceptors, etc. Cre recombination of the Ncor1^lox allele (86) eliminates only exons encoding the RID3 domain of the corepressor that is required for TR interaction without changing the reading frame. Therefore, the NCoR1^ΔID mutation preserves interactions with some other nuclear receptors and has limited developmental consequences. The mutation increases the sensitivity to T₃ stimulation of the cells, such as hepatocytes, in which NcoR is a predominant corepressor. IRES, internal ribosome entry site; PGK, phosphoglycerate kinase; RID, receptor interaction domain.