Trends in Endocrinology & Metabolism
Thyroid hormone receptors: lessons from knockout and knock-in mutant mice
Section snippets
TR loci are complex
TRs belong to the nuclear hormone receptor superfamily, and are encoded by only two genes [3]: TRα and TRβ [NR1A1 and NR1A2 according to nuclear hormone receptor nomenclature (http://www.ens-lyon.fr/LBMC/laudet/pres-fr.htm); Thra and Thrb in the Mouse Genome Informatics database (http://www.informatics.jax.org/)]. Both loci are complex, with alternative promoter usage and alternative splicing resulting in four mRNA in each of the loci (Fig. 1). This leads to the synthesis of four nuclear
TR knockout: a difficult dilemma
Experience indicates that TR knockout design is of crucial importance in determining the phenotype outcome. A first putative source of artifacts, and a liability of the knockout approach, is the creation of short N-terminal products when translation initiation codons are preserved. Detection challenge makes the existence of such truncated products difficult to rule out. The insertion of foreign sequences, usually a drug selection cassette, can also unpredictably alter locus regulation. These
TR knock-in
Two TRβ knock-in mutations were created to reproduce the human genetic disease known as resistance to thyroid hormone (RTH) [15]. The Δ337T single amino acid deletion abrogates ligand binding and transforms the TRβ receptors into constitutive repressors [16]. The PV frameshift mutation eliminates the C-terminal activation function (AF-2 domain) necessary for trans-activation and reduces ligand binding [17]. The same PV mutation was introduced in the TRα locus with a different result, with TRαPV
Phenotypic analysis
The phenotypes of single and interbred compound mutant mice have been meticulously analyzed by numerous investigators. TR mutations can have direct or indirect effects on most if not all functions and organs. The heart, liver, small intestine and central nervous system have been the focus of recent investigations. Although a complete description of this literature is beyond the scope of this review, most of these data have been reviewed recently 21, 22, 23. Here, we focus on what these studies
Contrasting function of TRα1 and TRβ receptors in mediating T3 signaling
The only primary developmental defect of Pax8−/− knockout mice is the absence of thyroid follicular cells [24]. This mutation thus results in congenital hypothyroidism, which is lethal in mice. Death occurs during the postnatal, pre-weaning weeks, a period normally characterized by a peak in hormone production [25], which is required for proper brain 26, 27, bone [28] and intestinal [29] maturation. During this crucial developmental period, which resembles T3-mediated amphibian metamorphosis,
TR respective function: tissue distribution vs receptor properties
With the noticeable exception of female sexual behavior [35], all the differences between TRα and TRβ mutants can be explained by differences in either expression pattern or intrinsic receptor properties. The first explanation holds for deafness, which is seen in TRβ−/− knockouts [30], and correlates with a preferential expression of TRβ in the inner ear. Similarly, the dominant-negative effect of the TRβPV knock-in mutation seems to be dictated by the TRβ gene expression pattern [36].
TR aporeceptor function
Because TR are type II nuclear hormone receptors, they can bind DNA in a ligand-independent manner. In vitro studies have shown that unliganded TR, the aporeceptor, can exert a negative effect on transcription by recruiting corepressor complexes with histone deacetylase activity [42]. Genetic analysis of mice confirms the importance of this process in vivo. For example, Pax8−/− mice lack only thyroid follicular cells and do not survive for more than three weeks without hormone rescue, whereas
Function of the TR isoforms that do not bind T3
A concerted effort has been made to understand the possible function of the non-ligand-binding TRα isoforms, because most of the locus mRNA encodes protein with TR antagonist properties. Although it is a poor RXR heterodimer partner, TRα2 can bind DNA, but cannot bind T3. It is able to exert a negative effect on T3-response element-mediated transcription in transfected cells. Its in vivo function has not been established. TRα2−/− animals display increased sensitivity to T3, but this could be
Future directions
The almost complete sequencing of the human and mouse genomes leads to the comforting conclusion that only two genes are sufficient to drive the diverse T3 genomic response. However, because all cells seem to be sensitive to T3 action at some level, and as new possibilities for investigation become available, the phenotype analysis of the mutants presented here will certainly continue to aid our understanding of in vivo T3 action. For example, kidney, pancreas and skin are organs in which known
Acknowledgements
We thank K. Gauthier and A. Shulman for critical reading of the article and D. Forrest for communication of in press publications.
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