Disease relevance of Foxe1

• The Foxe1 protein is also expressed in human and mouse basal cell carcinoma in which hedgehog signaling is constitutively activated, whereas it is undetectable in normal epidermis and squamous cell carcinoma [1].
• Here we show that Titf2-null mutant mice exhibit cleft palate and either a sublingual or completely absent thyroid gland [2].
• Thus, mutation of Titf2-/- results in neonatal hypothyroidism that shows similarity to thyroid dysgenesis in humans [2].
• In humans, mutations of the gene encoding for thyroid transcription factor-2 (TTF-2) result in the Bamforth syndrome, characterized by thyroid agenesis, cleft palate, spiky hair, and choanal atresia [3].
• We performed a genetic analysis of the TTF-2 gene in 2 children with congenital hypothyroidism (CH) and cleft palate, 45 children with thyroid dysgenesis, 19 children with isolated cleft palate or cleft lip, 4 patients with thyroid hemiagenesis [4].

High impact information on Foxe1

• TTF-2 is a member of the forkhead/winged-helix domain transcription factor family, many of which are key regulators of embryogenesis [5].
• 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 [2].
• 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 [6].
• 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 [6].
• The forkhead transcription factor FOXE1 is mutated in patients with Bamforth-Lazarus syndrome that exhibit hair follicle defects, suggesting a possible role for Foxe1 in hair follicle morphogenesis [1].

Biological context of Foxe1

• Requirement of the forkhead gene Foxe1, a target of sonic hedgehog signaling, in hair follicle morphogenesis [1].

Anatomical context of Foxe1

• Moreover, by the generation of mouse mutants expressing Foxe1 exclusively in the thyroid primordium, we provide a better understanding of the role of Foxe1 in these cells in order to acquire the competence to migrate into the underlying mesenchyme [7].
• Three genes, TTF1, TTF2, and PAX8, involved in thyroid gland development and migration have been identified [8].
• Strikingly, TTF-1- and TTF-2-positive cells aberrantly develop in the presumptive trachea of Shh-/- embryos [9].
• According to this expression, at E13.5, TTF-2 is present in endoderm derivatives, such as tongue, palate, epiglottis, pharynx, and oesophagus [3].
• At embryonic day (E) 10.5, TTF-2 is expressed in Rathke's pouch, in thyroid, and in the epithelium of the pharyngeal wall and arches, whereas it is absent in the epithelium of the pharyngeal pouches [3].

Associations of Foxe1 with chemical compounds

• Direct sequencing of the TTF-2 gene revealed polymorphisms in the length of the polyalanine tract [4].

Other interactions of Foxe1

• Thyroid-specific transcription factors (TTF-1 and TTF-2) and thyroglobulin are expressed indicating terminal differentiation [9].

References