A mouse model for hereditary thyroid dysgenesis and cleft palate

Abstract

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.

Origin of the ultimobranchial body cyst: T/ebp/Nkx2.1 expression is required for development and fusion of the ultimobranchial body to the thyroid

“…A homeodomain transcription factor, T/ebp (also called Ttf1, Titf1, or Nkx2.1) (Guazzi et al, 1990;Mizuno et al, 1991), is one of the transcription factors essential for regulating the expression of genes involved in thyroid hormone synthesis as well as thyroid organogenesis (Kimura et al, 1996;De Felice et al, 1998;Mansouri et al, 1998;Damante et al, 2001;Di Lauro and De Felice, 2001;De Felice and Di Lauro, 2004). Mice carrying a null mutation for T/ebp gene die at birth due to profoundly hypoplastic lungs, a defective hypothalamus, and absence of the thyroid and pituitary glands (Kimura et al, 1996).…”

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 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). In humans, mutations of the gene encoding for TTF-2 result in the Bamforth syndrome, characterized by thyroid agenesis, cleft palate, spiky hair, and choanal atresia (Clifton-Bligh et al, 1998).…”

Morphogenesis of the thyroid gland

“…Mice deficient of Nkx2-1, Pax8, Foxe1 or Hhex are well-studied models of athyreosis, i.e. the primordium is correctly specified but eventually regresses leading to a lack of thyroid tissue in late stages of development (Kimura et al, 1996;Mansouri et al, 1998;De Felice et al, 1998;Martinez Barbera et al, 2000). These transcription factors are thus not individually required for thyroid specification or early bud formation.…”

“…Foxe1 deficient mice are born at an expected ratio but die in the early postnatal period, probably due to the severe cleft palate (De Felice et al, 1998). No orthotopic thyroid is present and hormone analysis reveals severe CH.…”

“…In early thyroid morphogenesis a rudimentary bud is formed but its fate is variable: in 50% of the embryos the thyroid bud retains a position at the base of the prospective tongue, present also in late development (E15.5), whereas in the remainder cases no thyroid is found at all. It has therefore been proposed that Foxe1 specifically regulates the migration of the mouse thyroid primordium after detachment of the bud, besides supporting progenitor cell survival (De Felice et al, 1998), which will be discussed in further detail below (migration section). In contrast, no thyroid phenotype has been identified after knock-down of a recently characterized zebrafish Foxe1 ortholog (see below) (Nakada et al, 2009).…”