Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland

Abstract

The thyroid-stimulating hormone͞thyrotropin (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 TSH͞TSHR 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 TSHRknockout 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 sodium͞iodide 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 TSH͞TSHR pathway is in controlling genes involved in iodide metabolism such as sodium͞iodide 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. T he mouse thyroid gland begins to develop at embryonic day (E)8.5 as an endodermal thickening in the floor of the primitive pharynx. After loosing all connections with the pharynx, the thyroid bud migrates caudally, reaching its final position in front of the trachea ϷE13 (1). Only after completion of migration do thyroid follicular cells begin their differentiative program and express thyroid-specific genes such as thyroglobulin (Tg), thyroid-stimulating hormone͞thyrotropin (TSH) receptor (TSHR), thyroperoxidase (TPO), and the sodium͞iodide symporter (NIS) (2). Finally, primitive follicles appear, and the gland displays its final morphological organization. Since E8.5, thyroid precursor cells express a combination of transcription factors such as TTF-1 (encoded by the titf1͞nkx2.1 gene) (3), TTF-2 (encoded by the titf2͞foxe1 gene) (4), and Pax8 (5). Gene-targeting experiments demonstrated that all these factors are required for the early stages of thyroid development (6-8). However, it still is unclear what the mechanisms are that lead to the initiation of functional differentiation that only occurs at E14.TSH is known as the main regulator of the adult thyroid gland. Indeed, after binding to its receptor, TSH stimulates the thyroid cells in almost every aspect of their metabolism including synthesis and secretion of thyroid hormones (9). Several groups have demonstrated clearly that TSH regulates mRNA levels of several thyroid-specific genes such as Tg (10-13), TPO (13-15), and NIS (16,17).TSH also stimulates the aggregation of porcine thyroid cells in follicles (18), and its presence is necessary to maintain the follicular architecture (19). In the rat, there is a temporal correlation between the increased expression of TSHR and the formation of follicles. Indeed, TSHR mRNA is expressed by E15 (3, 20), and its expression increases on E17-E18. At this stage, thyroid-speci...

Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5

“…Although neither TSH nor the TSHR are required for the initial formation of the thyroid gland during development (42), the lack of signaling through the TSHR leads to thyroid hypoplasia in mature animals (1,(43)(44)(45), and overstimulation of cAMP production in the thyroid either artificially (46)(47)(48) or by stimulation of the TSHR (49, 50) leads to thyroid hyperplasia. However, we found the thyroid glands of OGH-TG mice to be grossly normal in weight and appearance.…”

Analysis of origin and growth of the thyroid gland in zebrafish

“…Alternatively, a nearly normal thyroid in lia mutant larvae reveals that, under wild-type conditions, Tsh does not play a major role in thyroid growth at these early larval stages. As judged from Tsh-receptor deficient mice that have a normal thyroid gland at birth, neither maternal nor zygotic Tsh is required for fetal thyroid growth in this species (Postiglione et al, 2002). Of interest, both early thyroid function (T4 immunostaining) and growth (a normal row of follicles) in zebrafish larvae is Tsh independent and, in this respect, similar to fetal thyroid growth in mice.…”

Thyroid targeting of the N-ras(Gln61Lys) oncogene in transgenic mice results in follicular tumors that progress to poorly differentiated carcinomas

“…TTF-1 is expressed by the Tg-N-ras hyperplastic follicular thyroid cells (i) as well as by follicular carcinoma cells (j). Briefly, 5 mm tissue sections were deparaffinized, alcohol-rehydrated, subjected to heat-induced antigen retrieval and incubated overnight with anti-Ki67/MIB-1 (1:50) (diaminobenzidine (DAB); Dako, Carpinteria, CA, USA), TTF-1 (Dako Corporation), Tg (Dako Corporation), PAX-8 or NIS antibodies (Postiglione et al, 2002). Then, the slides were incubated with biotinylated anti-immunoglobulin (Ig)G and with pre-mixed avidinbiotin complex (Vectostain ABC kits, Vector Laboratories, Burlingame, CA, USA).…”