A MOUSE MODEL FOR HEREDITARY THYROID DYSGENESIS AND CLEFT-PALATE

Alteration of thyroid gland morphogenesis (thyroid dysgenesis) is a fr equent human malformation. Among the one in three to four thousand new borns in which congenital hypothyroidism is detected, 80% have either an ectopic, small and sublingual thyroid, or have no thyroid tissue(1) . Most of these cases appear sporadically, although a few cases of rec urring familial thyroid dysgenesis have been described(2). The lack of evidence for hereditary thyroid dysgenesis may be due to the severity of the hypothyroid phenotype. Neonatal screening and early thyroid ho rmone therapy have eliminated most of the clinical consequences of hyp othyroidism such that the heritability of this condition may become ap parent in the near future. We have recently cloned cDNA encoding a for khead 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 for egut endoderm and in craniopharyngeal ectoderm, including Rathke's pou ch(3). Expression of Titf2 in thyroid cell precursors is down-regulate d as they cease migration, suggesting that this factor is involved in the process of thyroid gland morphogenesis. Here we show that Titf2-nu ll mutant mice exhibit cleft palate and either a sublingual or complet ely absent thyroid gland. Thus, mutation of Titf2(-/-) results in neon atal hypothyroidism that shows similarity to thyroid dysgenesis in hum ans.