ABSTRACT
The thyroid-stimulating hormone/thyrotropin (TSH) is the most relevant hormone in the control of thyroid gland physiology in adulthood. TSH effects on the thyroid gland are mediated by the interaction with a specific TSH receptor (TSHR). We studied the role of TSHTSHR signaling on gland morphogenesis and differentiation in the mouse embryo using mouse lines deprived either of TSH (pit(dw)pit(dw)) or of a functional TSHR (tshr(hyt)tshr(hyt) and TSHR-knockout lines). The results reported here show that in the absence of either TSH or a functional TSHR, the thyroid gland develops to a normal size, whereas the expression of thyroperoxidase and the sodium/iodide symporter are reduced greatly. Conversely, no relevant changes are detected in the amounts of thyroglobulin and the thyroid-enriched transcription factors TTF-1, TTF-2, and Pax8. These data suggest that the major role of the TSH/TSHR pathway is in controlling genes involved in iodide metabolism such as sodium/iodide symporter and thyroperoxidase. Furthermore, our data indicate that in embryonic life TSH does not play an equivalent role in controlling gland growth as in the adult thyroid.
Subject(s)
Gene Expression Regulation, Developmental/physiology , Receptors, Thyrotropin/physiology , Signal Transduction/physiology , Thyroid Gland/embryology , Thyrotropin/physiology , Animals , Antigens, Differentiation/biosynthesis , Antigens, Differentiation/genetics , Cell Differentiation , Crosses, Genetic , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Forkhead Transcription Factors , Gestational Age , Humans , Hypothyroidism/embryology , Hypothyroidism/genetics , Iodide Peroxidase/biosynthesis , Iodide Peroxidase/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Morphogenesis , Nuclear Proteins/biosynthesis , Nuclear Proteins/genetics , Organ Size , PAX8 Transcription Factor , Paired Box Transcription Factors , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, Thyrotropin/deficiency , Receptors, Thyrotropin/genetics , Recombinant Fusion Proteins/physiology , Repressor Proteins/biosynthesis , Repressor Proteins/genetics , Symporters/biosynthesis , Symporters/genetics , Thyroglobulin/biosynthesis , Thyroglobulin/genetics , Thyroid Gland/growth & development , Thyroid Gland/pathology , Thyroid Nuclear Factor 1 , Thyrotropin/deficiency , Thyrotropin/genetics , Trans-Activators/biosynthesis , Trans-Activators/genetics , Transcription Factors/biosynthesis , Transcription Factors/geneticsABSTRACT
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.
