TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation

Abstract

Expression of thyroglobulin (Tg) and thyroperoxidase (TPO) genes in thyroid follicular cells occurs in the mouse at embryonic day (E)14.5. Two transcription factors, TTF-1 and Pax-8, have been implicated in transcriptional activation of Tg and TPO, even though the onset of their expression is at E9.5, suggesting that additional events are necessary for transcriptional activation of Tg and TPO genes. We report in this paper the cloning of TTF-2, a DNA binding protein that recognizes sites on both Tg and TPO promoters. TTF-2 is a new forkhead domain-containing protein whose expression is restricted to the endodermal lining of the foregut and to the ectoderm that will give rise to the anterior pituitary. TTF-2 shows transient expression in the developing thyroid and anterior pituitary. In the thyroid, TTF-2 expression is down-regulated just before the onset of Tg and TPO gene expression, suggesting that this transcription factor plays the role in development of a negative controller of thyroid-specific gene expression.

Distribution of the titf2/foxe1 gene product is consistent with an important role in the development of foregut endoderm, palate, and hair

“…TTF-2 mRNA is present in the posterior stomodeum, in the dorsal ectoderm, and in Rathke's pouch (Zannini et al, 1997). In the present study, we confirm the transient expression of TTF-2 protein in pituitary gland and we report, for the first time, the presence of TTF-2 in two other ectoderm derivatives: nasal choanae and whiskers.…”

“…It was demonstrated previously that, at early stage of embryogenesis, TTF-2 mRNA is expressed in the epithelial layer of the foregut and in the thyroid anlage (Zannini et al, 1997). To better understand the role of TTF-2 during organogenesis, we have analyzed in detail its expression by using a TTF-2-specific antibody.…”

“…Zannini et al (1997) cloned the rat cDNA encoding TTF-2 and demonstrated that TTF-2 is a 42-kDa forkhead-containing protein highly enriched in thyroid follicular cells. TTF-2, encoded by the titf2/ foxe1 gene, is a promoter-specific transcriptional repressor (Zannini et al, 1997) that displays both promoter and transcriptional activation domain specificity (Perrone et al, 2000).…”

“…Forkhead genes have been also identified as factors that bind to regulatory elements in mammalian genes expressed in terminally differentiated cells . TTF-2 mRNA is expressed in the endoderm lining the foregut, in the developing thyroid, and in the ectoderm that gives rise to the anterior pituitary (Zannini et al, 1997;Parlato et al, 2001). Gene targeting experiments have demonstrated that titf2/foxe1 null mice exhibit cleft palate and either a sublingual or completely absent thyroid gland (De Felice et al, 1998).…”

Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation

“…Studies on the TG and TPO promoters have allowed the identi®cation of three thyroid-speci®c transcription factors, TTF-1 (Thyroid Transcription Factor-1), TTF-2 (Thyroid Transcription Factor-2) and Pax-8 (belonging to the family of the paired domain proteins), involved in the onset and maintenance of the di erentiation status (Guazzi et al, 1990;Zannini et al, 1992Zannini et al, , 1997. These transcription factors are expressed during thyroid development, in the adult gland, as well as in a few other sites and their concomitant expression is unique to thyroid cells (Civitareale et al, 1989;Lazzaro et al, 1991;Missero et al, 1997;Zannini et al, 1997).…”