Alteration of thyroid gland morphogenesis (thyroid dysgenesis) is a frequent human malformation. Among the one in three to four thousand newborns in which congenital hypothyroidism is detected, 80% have either an ectopic, small and sublingual thyroid, or have no thyroid tissue. Most of these cases appear sporadically, although a few cases of recurring familial thyroid dysgenesis have been described. The lack of evidence for hereditary thyroid dysgenesis may be due to the severity of the hypothyroid phenotype. Neonatal screening and early thyroid hormone therapy have eliminated most of the clinical consequences of hypothyroidism such that the heritability of this condition may become apparent in the near future. We have recently cloned cDNA encoding a forkhead domain-containing transcription factor, TTF-2, and have located the position of the gene, designated Titf2, to mouse chromosome 4 (ref. 3). Titf2 is expressed in the developing thyroid, in most of the foregut endoderm and in craniopharyngeal ectoderm, including Rathke's pouch. Expression of Titf2 in thyroid cell precursors is down-regulated as they cease migration, suggesting that this factor is involved in the process of thyroid gland morphogenesis. Here we show that Titf2-null mutant mice exhibit cleft palate and either a sublingual or completely absent thyroid gland. Thus, mutation of Titf2-/- results in neonatal hypothyroidism that shows similarity to thyroid dysgenesis in humans.

Only three of the four thyroid hormone receptor (TR) isoforms, ␣1, ␤1, and ␤2, bind thyroid hormone (TH) and are considered to be true TRs. TR␣2 binds to TH response elements on DNA, but its role in vivo is still unknown. We produced mice completely deficient in TR␣ (TR␣ o/o ) that maintain normal serum thyroid-stimulating hormone (TSH) concentration despite low serum thyroxine (T4), suggesting increased sensitivity to TH. We therefore examined the effects of TH (L-3,3 ,5-triiodothyronine, L-T3) given to TH-deprived and to intact TR␣ o/o mice. Controls were wild-type (WT) mice of the same strain and mice resistant to TH due to deficiency in TR␤ (TR␤ ؊/؊ ). In liver, T3 produced significantly greater responses in TR␣ o/o and smaller responses in TR␤ ؊/؊ as compared with WT mice. In contrast, cardiac responses to L-T3 were absent or reduced in TR␣ o/o , whereas they were similar in WT and TR␤ ؊/؊ mice, supporting the notion that TR␣1 is the dominant TH-dependent TR isoform in heart. 5-Triiodothyronine (L-T3) given to intact mice produced a greater suppression of serum T4 in TR␣ o/o than it did in WT mice and reduced by a greater amount the TSH response to TSH-releasing hormone. This is an in vivo demonstration that a TR deficiency can enhance sensitivity to TH. This effect is likely due to the abrogation of the constitutive ''silencing'' effect of TR␣2 in tissues expressing the TR␤ isoforms.T hyroid hormone (TH) action is mediated through specific nuclear TH receptors (TRs) functioning as ligand-dependent transcription factors that increase or decrease the expression of target genes (1-3). There are two TR genes. The TR␤ locus generates the ␤1 and ␤2 receptors by using two different promoters and alternative splicing. The TR␣ locus encodes TR␣1, a molecule containing 410 aa, and three proteins that do not bind the ligand, triiodothyronine (T 3 ) (4-7) (GenBank accession no. AI322342). TR␣2, which results from an alternative splicing of the TR␣ primary transcript, has 492 aa, the first 370 of which are identical to TR␣1. TR⌬␣1 and TR⌬␣2, molecules of approximately 154 and 237 aa, respectively, are generated from an internal promoter located in intron 7 of the TR␣ locus (6). The function of TR␣2, which has a wide tissue distribution (8), and that of TR⌬␣1 and TR⌬␣2, found mainly in brain, gut, and lung (6), are still unknown. However, all have been shown to inhibit ligand-dependent transactivation of TR␤ and TR␣1, a phenomenon termed the dominant negative effect (6, 9-11, ** ).The relative contribution of the two TR gene products in mediating TH responses is poorly understood because of the paucity of information regarding in vivo function. In vitro DNA binding studies and functional assays in transfected cells have generated conflicting results concerning the specific effect of TR isoforms in gene regulation (12, 13). Interpretation is complicated, however, because data are derived from artificial systems using the overexpression of chimeric gene constructs that may not be faithful models of events occurring in the...

Congenital hypothyroidism with thyroid dysgenesis (TD) is a frequent human condition characterized by elevated levels of TSH in response to reduced thyroid hormone levels. Congenital hypothyroidism is a genetically heterogeneous disease. In the majority of cases studied, no causative mutations have been identified and very often the disease does not show a Mendelian transmission. However, in approximately 5% of cases, it can be a consequence of mutations in genes encoding the TSH receptor or the transcription factors TITF1, FOXE1, or PAX8. We report here that in mouse models, the combination of partial deficiencies in the Titf1 and Pax8 genes results in an overt TD phenotype that is absent in either of the singly deficient, heterozygous mice. The disease is characterized by a small thyroid gland, elevated levels of TSH, reduced thyroglobulin biosynthesis, and high occurrence of hemiagenesis. The observed phenotype is strain specific, and the pattern of transmission indicates that at least two other genes, in addition to Titf1 and Pax8, are necessary to generate the condition. These results show that TD can be of multigenic origin in mice and strongly suggest that a similar pathogenic mechanism may be observed in humans.

Only three of the four thyroid hormone receptor (TR) isoforms, alpha1, beta1, and beta2, bind thyroid hormone (TH) and are considered to be true TRs. TRalpha2 binds to TH response elements on DNA, but its role in vivo is still unknown. We produced mice completely deficient in TRalpha (TRalpha(o/o)) that maintain normal serum thyroid-stimulating hormone (TSH) concentration despite low serum thyroxine (T(4)), suggesting increased sensitivity to TH. We therefore examined the effects of TH (L-3,3',5-triiodothyronine, L-T3) given to TH-deprived and to intact TRalpha(o/o) mice. Controls were wild-type (WT) mice of the same strain and mice resistant to TH due to deficiency in TRbeta (TRbeta(-/-)). In liver, T3 produced significantly greater responses in TRalpha(o/o) and smaller responses in TRbeta(-/-) as compared with WT mice. In contrast, cardiac responses to L-T3 were absent or reduced in TRalpha(o/o), whereas they were similar in WT and TRbeta(-/-) mice, supporting the notion that TRalpha1 is the dominant TH-dependent TR isoform in heart. 5-Triiodothyronine (L-T3) given to intact mice produced a greater suppression of serum T(4) in TRalpha(o/o) than it did in WT mice and reduced by a greater amount the TSH response to TSH-releasing hormone. This is an in vivo demonstration that a TR deficiency can enhance sensitivity to TH. This effect is likely due to the abrogation of the constitutive "silencing" effect of TRalpha2 in tissues expressing the TRbeta isoforms.

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